Aryl imidazoles and related compounds as C5a receptor modulators

ABSTRACT

The invention provides packaged pharmaceutical preparations of Aryl substituted imidazoles, pyrazoles, pyridizines and related compounds of the Formula 
                         
where the variables are defined herein.
 
     Such compounds are ligands of C5a receptors. Preferred compounds of the invention act bind to C5a receptors with high affinity and exhibit neutral antagonist or inverse agonist activity at C5a receptors. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating a variety of inflammatory and immune system disorders.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This application is a divisional of patent application U.S. Ser. No.10/405,989, now U.S. Pat. No. 7,186,734, filed Mar. 28, 2003, whichclaims priority from U.S. Provisional Application Ser. No. 60/369,112filed Mar. 29, 2002 and U.S. Provisional Application Ser. No. 60/392,145filed Jun. 26, 2002, each of which is incorporated by reference.

FIELD OF THE MENTION

This invention includes substituted aryl imidazoles and relatedcompounds that modulate a mammalian complement C5a receptor. Certaincompounds provided herein act as high affinity C5a receptor ligandsand/or act as antagonists (including inverse agonists) of complement C5areceptors, preferably human C5a receptors. This invention also relatesto pharmaceutical compositions comprising such compounds, and to the useof such compounds for treating a variety of inflammatory and immunesystem disorders. Additionally, fibs invention relates to the use suchcompounds as probes for the localization of C5a receptors.

BACKGROUND OF THE INVENTION

C5a, a 74 amino acid peptide, is generated in the complement cascade bythe cleavage of the complement protein C5 by the complement C5convertase enzyme. C5a has both anaphylatoxic (e.g., bronchoconstrictingand vascular spasmogenic) and chemotactic effects. Therefore, it isactive in engendering both the vascular and cellular phases ofinflammatory responses. Because it is a plasma protein and, therefore,generally almost instantly available at a site of an inciting stimulus,it is a key mediator in terms of initiating the complex series of eventsthat results in augmentation and amplification of an initialinflammatory stimulus. The anaphylatoxic and chemotactic effects of theC5a peptide are believed to be mediated through its interaction with theC5a receptor (CD88 antigen), a 52 kD membrane bound G-protein coupledreceptor (GPCR). C5a is a potent chemoattractant for polymorphonuclearleukocytes, bringing neutrophils, basophils, eosinophils and monocytesto sites of inflammation and/or cellular injury. C5a is one of the mostpotent chemotactic agents known for a wide variety of inflammatory celltypes. C5a also “primes” or prepares neutrophils for variousantibacterial functions (e.g., phagocytosis). Additionally, C5astimulates the release of inflammatory mediators (e.g., histamines,TNF-α, IL-1, IL-6, IL-8, prostaglandins, and leukotrienes) and therelease of lysosomal enzymes and other cytotoxic components fromgranulocytes. Among its other actions, C5a also promotes the productionof activated oxygen radicals and the contraction of smooth muscle.

Considerable experimental evidence implicates increased levels of C5a ina number of autoimmune diseases and inflammatory and related disorders.

Agents that block the binding of C5a to its receptor other agents,including inverse agonists, which modulate signal transductionassociated with C5a-receptor interactions, can inhibit the pathogenicevents, including chemotaxis, associated with anaphylatoxin activitycontributing to such inflammatory and autoimmune conditions.

SUMMARY OF THE INVENTION

The present invention provides substituted aryl imidazoles and relatedcompounds of Formula I, below. Such compounds are useful as modulatorsof C5a receptor and preferably inhibit C5a receptor activation and/orC5a receptor-mediated signal transduction.

The invention provides compounds of Formula I:

and the pharmaceutically acceptable salts thereof, wherein the ringsystem represented by

is a 5 membered heteroaryl ring system, in which x is 0, A is chosenfrom carbon and heteroatoms nitrogen, oxygen, and sulfur, and E and Gare independently carbon or nitrogen, provided that the 5 memberedheteroaryl ring system does not contain more than 3 heteroatoms or morethan 1 oxygen or sulfur atom, or a 6 membered heteroaryl ring, system,in which x is 1, and A, B, E, and G are independently chosen from carbonand nitrogen, provided that the 6 membered heteroaryl ring system doesnot contain more than 3 mLrogen atoms.

R and R₁ independently represent:

i) hydrogen, hydroxy, halogen, amino, cyano, nitro, —CHO, —CONH₂,C₁-C₆haloalkyl, or C₁-C₆haloalkoxy,

ii) C₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆alkynyl, C₁-C₆alkanoyl, C₁-C₆alkoxy,C₃-C₇cycloalkyl, (C₃-C₇cycloalkyl)C₁-C₄alkyl, mono- ordi-C₁-C₆alkylamino, mono- or di-C₁-C₆alkylaminoC₁-C₆alkyl, mono- ordi-C₁-C₆alkylcarboxamide, C₁-C₆alkoxycarbonyl, —SO_(n)(C₁-C₆alkyl),—NHSO_(n)C₁-C₆alkyl, —SO_(n)N(C₁-C₆alkyl) (C₁-C₆alkyl), phenyl-SO_(n)—,each of which is optionally substituted, or

iii) naphthyl, phenyl, phenylC₁-C₄carbhydryl, 5- or 6-memberedheteroaryl, or 5- or 6-membered heteroarylC₁-C₄carbhydryl, each of whichis optionally substituted.

When E is Nitrogen, R₂, is chosen from C₁-C₇alkyl, C₂-C₇alkenyl,C₂-C₇alkynyl, C₃-C₇cycloalkyl(C₁-C₄allyl), benzyl, and C₁-C₆haloalkyl,each of which is optionally substituted; and when E is Carbon, R₂ ischosen from (i) hydrogen, halogen, hydroxy; C₁-C₆haloalkyl, andC₁-C₆haloalkoxy, and (ii) C₃-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl,C₁-C₇ alkoxy, C₁-C₇alkylamino, C₃-C₇cycloalkyl(C₁-C₄alkyl), and benzyl;each of which is optionally substituted;

R₃ is hydrogen, C₁-C₆alkyl, C₂-C₆ alkenyl, C₁-C₆hydroxyalkyl,C₁-C₆haloalkyl, C₃-C₇cycloalkyl, (C₃-C₇cycloalkyl)C₁-C₄alkyl, orphenyl(C₁-C₄alkyl).

When x is 0, R₁, and R₃ may be joined to form an optionally substitutedcycloalkyl ring having from 3 to 7 carbon atoms.

R₄ is C₁-C₆alkyl, C₂-C₆ alkenyl, C₁-C₆ alkynyl, C₃-C₇ cycloalkyl, C₃-C₇cycloalkenyl, (C₃-C₇cycloalkyl)C₁-C₄alkyl,(C₃-C₇cycloalkenyl)C₁-C₄alkyl, or hexahydro-1,3-benzodioxolylmethyl,each of which is optionally substituted; or

R₄ is

(i) optionally substituted arylC₀-C₄alkyl having from 1 ring or 2 fusedor pendant rings,

(ii) an arylC₁-C₄alkyl group, wherein the aryl portion is fused to a 5to 7 membered saturated or partially unsaturated ring that (a) has 0, 1or 2 ring atoms independently chosen from N, O and S, with remainingring atoms being carbon, and (5) is substituted with from 0 to 3substituents independently chosen from halogen, alkyl, alkoxy,haloalkyl, and haloalkoxy,

(iii) optionally substituted heterocycloalkyl(C₀-C₄alkyl),

(iv) optionally substituted heteroarylC₀-C₂alkyl, having 1 ring or 2fused or pendant rings, from 5 to 7 members in each ring, and in atleast one ring 1 to 3 heteroatoms selected from N, O, and S, or

(v) optionally substituted saturated or partially unsaturatedheterocyclic(C₀-C₄alkyl) wherein the heterocyclic portion has from 4 to7 ring members, 1 or 2 of which ring members are N, S or O, withremaining ring members being carbon. R₅ and R₆ are independently chosenfrom hydrogen and C₁-C₆alkyl, and z is 1, 2, or 3. Ar₁ represents (i)optionally substituted aryl, (ii) optionally substituted phenyl fused toa 5- to 7-membered saturated or partially unsaturated ring that (a) has0, 1 or 2 ring atoms independently chosen from N, O and S, withremaining ring atoms being carbon, and (b) is substituted with from 0 to3 substituents independently chosen from halogen, alkyl, alkoxy,haloalkyl, and haloalkoxy, or (iii) optionally substituted heteroaryl,having 1 ring or 2 fused or pendant rings, from 5 to 7 members in eachring, and in at least one ring 1 to 3 heteroatoms selected from N, O,and S.

Ar₂ represents:

(i) C₃-C₇cycloalkyl, C₃-C₇cycloalkyl(C₁-C₄alkyl), C₃-C₇cycloalkenyl,C₃-C₇cycloalkenyl(C₁-C₄alkyl), or hexahydro-1,3-benzodioxolyl, each ofwhich is optionally substituted

(ii) an optionally substituted aryl having 1 ring or 2 fused or pendantrings,

(iii) an optionally substituted phenyl fused to a 5- to 7-memberedsaturated or partially unsaturated ring that (a) has 0, 1 or 2 ringatoms independently chosen from N, O and S, with remaining ring atomsbeing carbon, and (b) is substituted with from 0 to 3 substituentsindependently chosen from halogen, alkyl, alkoxy, haloalkyl, andhaloalkoxy, or

(iv) optionally substituted heteroaryl, having 1 ring or 2 fused orpendant rings, from 5 to 7 members in each ring, and in at least onering 1 to 3 heteroatoms selected from N, O, ad S.

In Formula I n is independently chosen from 0, 1, or 2; and y is aninteger of from 1 to 6.

DETAILED DESCRIPTION OF THE INVENTION

Chemical Description and Terminology

Compounds of the present invention are generally described usingstandard nomenclature.

The term “aryl imidazole,” as used herein, encompasses all compoundsthat satisfy one or more of Formulas I, IA, and II-XIV herein, as wellas pharmaceutically acceptable salts, prodrugs and hydrates of suchcompounds.

Certain compounds described herein contain one or more asymmetricelements such as stereogenic centers, stereogenic axes and the like(e.g., asymmetric carbon atoms) so that the compounds can exist indifferent stereoisomeric forms. These compounds can be, for example,racemates or optically active forms. For compounds with two or moreasymmetric elements, these compounds can additionally be mixtures ofdiastereomers. Unless otherwise specified all optical isomers andmixtures thereof are encompassed for compounds having asymmetriccenters. In addition, compounds with carbon-carbon double bonds mayoccur in Z- and a E-forms, with all isomeric forms of the compoundsbeing included in the present invention unless otherwise specified.Where a compound exists in various tautomeric forms, the invention isnot limited to any one of the specific tautomers, but rather encompassesall tautomeric forms.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample, and without limitation, isotopes of hydrogen include tritiumand deuterium and isotopes of carbon include ¹¹C, ¹³C, and ¹⁴C.

Certain compounds are described herein using a general formula, such asFormula I, which includes variables, such as Ar¹, R₁, and R₂Unlessotherwise specified, each variable within such a formula is definedindependently of other variables. Thus, for example, if a group is shownto be substituted with 0-2 R*, then said group may optionally besubstituted with up to two R* groups and R* at each occurrence isselected independently from the definition of R*. Also, combinations ofsubstituents and/or variables are permissible only if such combinationsresult in stable compounds.

A “substituent,” as used herein, refers to a molecular moiety that iscovalently bonded to an atom within a molecule of interest. For example,a “ring substituent” may be a moiety such as a halogen, alkyl group,haloalkyl group or other substituent discussed herein that is covalentlybonded to an atom (preferably a carbon or nitrogen atom) that is a ringmember. The term “substituted,” as used herein, means that any one ormore hydrogens on the designated atom is replaced with a selection fromthe indicated substituents, provided that the designated atom's normalvalence is not exceeded, and that the substitution results in a stablecompound (i.e., a compound that can be isolated, characterized andtested for biological activity). When a substituent is oxo (i.e., =0),then 2 hydrogens on the atom are replaced. When aromatic moieties aresubstituted by an oxo group, the aromatic ring is replaced by thecorresponding partially unsaturated ring. For example a pyridyl groupsubstituted by oxo is a tetrahydropyridone.

The phrase “optionally substituted” indicates that a group may either beunsubstituted or substituted at one or more of any of the availablepositions, typically 1, 2, 3, 4, or 5 positions, by one or more suitablesubstituents such as those disclosed herein. Various groups within thecompounds and formulae set forth herein are “optionally substituted”including, for example, R¹, R² and Ar¹. Optional substitution may alsobe indicated by the phrase “substituted with from 0 to X substituents,”in which X is the maximum number of substituents.

Suitable substituents include, for example, halogen, cyano, amino,hydroxy, nitro, azido, carboxamido, —COOH, SO₂NH₂, alkyl (e.g.,C₁-C₈alkyl), alkenyl (e.g., C₂-C₈alkenyl), alkynyl (e.g., C₂-C₈alkynyl),alkoxy (e.g., C₁-C₈alkoxy), alkyl ether (e.g., C₂-C₈alkyl ether),alkylthio (e.g., C₁-C₈alkylthio), mono- or di-(C₁-C₈alkyl)amino,haloalkyl (e.g., C₁-C₆haloalkyl), hydroxyalkyl (e.g.,C₁-C₆hydroxyalkyl), aminoalkyl (e.g., C₁-C₆aminoalkyl), haloalkoxy(e.g., C₁-C₆haloalkoxy), alkanoyl (e.g., C₁-C₈alkanoyl), alkanone (e.g.,C₁-C₈alkanone), alkanoyloxy (e.g., C₁-C₈alkanoyloxy), alkoxycarbonyl(e.g., C₁-C₈alkoxycarbonyl), mono- and di-(C₁-C₈alkyl)amino, mono- anddi-(C₁-C₈alkyl)aminoC₁-C₈alkyl, mono- and di-(C₁-C₈alkyl)carboxamido,mono- and di-(C₁-C₈alkyl)sulfonamido, alkylsulfinyl (e.g.,C₁-C₈alkylsulfinyl), alkylsulfonyl (e.g., C₁-C₈alkylsulfonyl), aryl(e.g., phenyl), arylalkyl (e.g., (C₆-C₁₈aryl)C₁-C₈alkyl, such as benzyland phenethyl), aryloxy (e.g., C₆-C₁₈aryloxy such as phenoxy),arylalkoxy (e.g., (C₆-C₁₈aryl)C₁-C₈alkoxy) and/or 3- to 8-memberedheterocyclic groups. Certain groups within the formulas provided hereinare optionally substituted with from 1 to 3, 1 to 4 or 1 to 5independently selected substituents.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups, and wherespecified, having the specified number of carbon atoms. Thus, the termC₁-C₆alkyl, as used herein, indicates an alkyl group having from 1 to 6carbon atoms. “C₀-C₄alkyl” refers to a bond or a C₁-C₄alkyl group. Alkylgroups include groups having from 1 to 8 carbon atoms (C₁-C₈alkyl), from1 to 6 carbon atoms (C₁-C₆alkyl) and from 1 to 4 carbon atoms(C₁-C₄alkyl), such as methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl,2-hexyl, 3-hexyl, and 3-methylpentyl. “Aminoalkyl” is an alkyl group asdefined herein substituted with one or more —NH₂ groups. “Hydroxyalkyl”is a hydroxy group as defined herein substituted with one or more —OHgroups.

“Alkenyl” refers to a straight or branched hydrocarbon chain comprisingone or more unsaturated carbon-carbon bonds, such as ethenyl andpropenyl. Alkenyl groups include C₂-C₈alkenyl, C₂-C₆alkenyl andC₂-C₄alkenyl groups (which have from 2 to 8, 2 to 6 or 2 to 4 carbonatoms, respectively), such as ethenyl, alkyl or isopropenyl.

“Alkynyl” refers to straight or branched hydrocarbon chains comprisingone or more triple carbon-carbon bonds. Alkynyl groups includeC₂-C₈alkynyl, C₂-C₆alkynyl and C₂-C₄alkyl groups, which have from 2 to8, 2 to 6 or 2 to 4 carbon atoms, respectively. Alkynyl groups includefor example groups such as ethynyl and propynyl.

“Alkoxy” represents an alkyl group as defined above with the indicatednumber of carbon atoms attached through an oxygen bridge. Examples ofalkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy,3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and3-methylpentoxy.

The term “alkanoyl” refers to an acyl group in a linear or branchedarrangement (e.g., —(C═O)-alkyl). Alklanoyl groups includeC₂-C₈alkanoyl, C₂-C₆alkanoyl and C₂-C₄alkanoyl groups, which have from 2to 8, 2 to 6, or 2 to 4 carbon atoms, respectively. “C₁alkanoyl” refersto —(C═O)—H, which (along with C₂-C₈alkanoyl) is encompassed by the term“C₁-C₈alkanoyl.”

The term, “alkyl ether” refers to a linear or branched ether substituentlinked via a carbon-carbon bond. Alkyl ether groups include C₂-C₈alkylether, C₂-C₆alkyl ether and C₂-C₆alkyl ether groups, which have 2 to 8,2 to 6, or 2 to 4 carbon atoms, respectively. By way of example, aC₂alkyl ether group has the structure —CH₂—O—CH₃.

The term “alkoxycabonyl” refers to an alkoxy group linked via a carbonyl(i.e., a group having the general structure —C(═O)—O-alkyl).Alkoxycarbonyl groups include C₂-C₈, C₂-C₆, and C₂-C₄alkoxycarbonylgroups, which have from 2 to 8, 2 to 6, or 2 to 4 carbon atoms,respectively. “C₁alkoxycarbonyl” refers to —C(═O)OH, and is compassed by“C₁-C₈alkoxycarbonyl.”

“Alkanoyloxy,” as used herein, refers to an alkanoyl group linked via anoxygen bridge (i.e., a group having the general structure—O—C(═O)-alkyl). Alkanoyloxy groups include C₂-C₈, C₂-C₆, andC₂-C₄alkanoyloxy groups, which have from 2 to 8, 2 to 6, or 2 to 4carbon atoms, respectively.

As used herein, the term “alkylthio” refers to an alkyl group attachedvia a thioether linkage. Alkylthio groups include C₁-C₈alkylthio,C₁-C₆alkylthio and C₁-C₄alkylthio, which have from 1 to 8, 1 to 6 or 1to 4 carbon atoms, respectively.

“Alkylsulfinyl,” as used herein, refers to an alkyl group attached via asulfinyl linkage. Alkylsulfinyl groups include C₁-C₈alkylsulfinyl,C₁-C₆alkylsulfinyl, and C₁-C₄alkylsulfinyl, which have from 1 to 8, 1 to6, and 1 to 4 carbon atoms, respectively.

By “alkylsulfonyl,” as used herein, is meant an alkyl group attached viaa sulfonyl linkage. Alkylsulfonyl groups include C₁-C₈alkylsulfonyl,C₁-C₆alkylsulfonyl, and C₁-C₄alkylsulfonyl, which have from 1 to 8, 1 to6, and 1 to 4 carbon atoms, respectively.

“Alkylamino” refers to a secondary or tertiary amine having the generalstructure —NH-alkyl or —N(alkyl)(alkyl), wherein each alkyl may be thesame or different. Such groups include, for example, mono- anddi-(C₁-C₈alkyl)amino groups, in which each alkyl may be the same ordifferent and may contain from 1 to 8 carbon atoms, as well as mono anddi-(C₁-C₆alkyl)amino groups and mono- and di-(C₁-C₄alkyl)amino groups.Alkylaminoalkyl refers to an alkylamino group linked via an alkyl group(i.e., a group having the general structure -alkyl-NH-alkyl or-alkyl-N(alkyl)(alkyl)). Such groups include, for example, mono- anddi-(C₁-C₈alkyl)aminoC₁-C₈alkyl, mono- anddi-(C₁-C₆alkyl)aminoC₁-C₆alkyl, and mono- anddi-(C₁-C₄alkyl)aminioC₁-C₄alkyl, in which each alkyl may be the same ordifferent.

The term “carboxamido” or “amido” refers to an amide group (i.e.,—(C═O)NH₂). “Alkylcarboxamido” refers to —NHC(═O)alkyl, preferably—NHC(═O)C₁-C₂alkyl.

“Carbhydryl” is intended to include both branched and straight-chainhydrocarbon groups, which is saturated or unsaturated, having thespecified number of carbon atoms.

The term “cycloalkyl” refers to hydrocarbon ring groups, having thespecified number of carbon atoms, usually from 3 to about 8 ring carbonatoms, or from. Cycloalkyl groups include C₃-C₈, and C₃-C₇ cycloalkylgroups, which have from 3 to 8 and 3 to 7 carbon atoms, respectively.Examples of cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl groups, as well as bridged and cagedsaturated ring groups such as norbornane or adamantane and the like.

In the term “(cycloalkyl)alkyl,” “cycloalkyl” and “alkyl” are as definedabove, and the point of attachment is on the alkyl group. This termencompasses, but is not limited to, cyclopropylmethyl, cyclohexylmethyl,and cyclohexylethyl.

The term “halogen” indicates fluorine, chlorine, bromine, or iodine.

“Haloalkyl” refers to both branched and straight-chain saturatedaliphatic hydrocarbon groups having the specified number of carbonatoms, substituted with 1 or more halogen atoms. Examples of haloalkylinclude, but are not limited to, trifluoromethyl, difluoromethyl,2-fluoroethyl, and penta-fluoroethyl.

“Haloalkoxy” indicates a haloalkyl group as defined above attachedthrough an oxygen bridge.

As used herein, the term “aryl” indicates aromatic groups containingonly carbon in the aromatic ring(s). Such aromatic groups may be furthersubstituted with carbon or non-carbon atoms or groups. Typical arylgroups contain 1 to 3 separate or fused rings, at least one of which isaromatic, and from 6 to about 18 ring atoms, without heteroatoms as ringmembers. Specifically preferred carbocyclic aryl groups include phenyland napthyl, including, 1-naphthyl and 2-naphthyl. When indicated,carbon atoms present within a carbocyclic ring may be optionallysubstituted with any of variety of ring substituents, as describedabove, or with specifically listed substituents.

The term “arylalkyl” refers to an aryl group is linked via an alkylgroup. Certain arylalkyl groups are (C₆-C₁₈aryl)C₁-C₈alkyl groups (i.e.groups in which a 6- to 18-membered aryl group is linked via aC₁-C₈alkyl group). Such groups include, for example, groups in whichphenyl or naphthyl is linked via a bond or C₁-C₈alkyl, preferably viaC₁-C₄alkyl, such as benzyl, 1-phenyl-ethyl, 1-phenyl-propyl and2-phenyl-ethyl.

The term “aryloxy” refers to an aryl group linked via a carbonyl (i.e.,a group having the general structure —(═O)—O-aryl). Phenoxy is arepresentative aryloxy group.

As used herein, the term “heteroaryl” is intended to indicate a stable5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclicheterocyclic ring which contains at least 1 aromatic ring that containsfrom 1 to 4 heteroatoms selected from N, O, and S, with remaining ringatoms being carbon. When the total number of S and 0 atoms in theheteroaryl group exceeds 1, then these heteroatoms are not adjacent toone another. It is preferred that the total number of S and 0 atoms inthe heterocycle is not more than 1, 2, or 3, more typically 1 or 2. Itis particularly preferred that the total number of S and O atoms in thearomatic heterocycle is not more than 1. Examples of heteroaryl groupsinclude pyridyl, furanyl, indolyl, pyrimidinyl, pyridizinyl, pyrazinyl,imidazolyl, oxazolyl, thienyl, thiazolyl, triazolyl, isoxazolyl,quinolinyl, pyrrolyl, pyrazolyl, and 5,6,7,8-tetrahydroisoquinoline.

The term “heterocyclic group” or “heterocycle” is used to indicatesaturated, partially unsaturated, or aromatic groups having 1 or 2rings, 3 to S atoms in each ring and in at least one ring between 1 and3 heteroatoms selected from N, O, and S. Any nitrogen or sulfurheteroatoms may optionally be oxidized. The heterocyclic group may beattached to its pendant group at any heteroatom or carbon atom thatresults in a stable structure. The heterocyclic groups described hereinmay be substituted on a carbon or nitrogen atom if the resultingcompound is stable. A nitrogen atom in the heterocycle may optionally bequaternized.

Representative examples of heteroaryl groups and heterocyclic groupsinclude, but are not limited to, acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl,carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl;-1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4, f-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, and xanthenyl.

“A C5a receptor” is a G-coupled protein receptor that specifically bindsC5a protein.

Preferably the C5a receptor is a human C5a receptor such as the proteinproduct of the sequence of the resulting PCR product described by Gerardand Gerard, (1991) Nature 349:614-17. The human C5a receptor may also bethat described by Boulay (1991) Biochemistry, 30(12): 2993-9 (GENBANKAccension No. M62505). Non-primate C5a receptors may be a rat C5areceptor such as a rat C5a receptor, GENBANK Accension Nos. X65862,Y09613, and AB003042, a canine C5a receptor, GENBANK Accension No.X65860, or a guinea pig C5a receptor, GENBANK Accension No. U86103.

A “C5a receptor modulator” is any compound that modulates C5a receptoractivation and/or activity (i.e., C5a receptor-mediated signaltransduction, as measured using a C5a receptor-mediated chemotaxis,radioligand binding assay, or calcium mobilization assay as providedherein). In certain embodiments, such a modulator may be exhibit anaffinity constant or IC₅₀ for binding to a C5a receptor of less than 1micromolar. In other embodiments the a C5a receptor modulator mayexhibit an affinity constant or IC₅₀ of less than 500 nM, 200 nM, 100nM, 50 nM, 25 nM, 10 nM or 5 nM in a standard C5a receptor-mediatedchemotaxis assay, radioligand binding, assay, or calcium mobilizationassay. A modulator may be a C5a receptor agonist or antagonist,although, for certain purposes described herein, a modulator preferablyinhibits C5a activation resulting from binding of C5a (i.e., themodulator is an antagonist). Preferred antagonists exhibit an antagonistIC₅₀ (which is used herein interchangeably with EC₅₀) of less than 1micromolar, preferably less than 100 nanomolar, in an assay of C5areceptor-mediated chemotaxis, radioligand binding, and/or calciummobilization. In addition, or alternatively, a modulator may act as aninverse agonist of C5a receptor. In certain embodiments, modulatorsprovided herein modulate activation and/or activity of a primate C5areceptor, such as human C5a receptor, which may be a cloned,recombinantly expressed receptor or a naturally expressed receptor. Fortreating non-human animals of any particular species, a compoundexhibiting high affinity for the C5a receptor of that particular speciesis preferred.

An “inverse agonist” of the C5a receptor is a compound which inhibitsthe activity of C5a at the C5a receptor, and reduces the activity of theC5a receptor below its basal activity level in the absence of added C5a.Inverse agonists of the C5a receptor may also inhibit binding of C5a tothe C5a receptor. The ability of a compound to inhibit the binding ofC5a to the C5a receptor may be measured by a binding assay, such as theradioligand binding assay given in Example 51. The basal activity of theC5a receptor may be determined from a GTP binding assay, such as theassay of Example 52. The reduction of C5a activity may also bedetermined from a GTP binding assay such as the assay of Example 52 or acalcium mobilization assay such as the assay of Example 53.

A “neutral antagonist” of the C5a receptor is a compound which inhibitsthe activity of C5a at the C5a receptor, but does not significantlychange the basal activity of the C5a receptor. Neutral antagonists ofthe C5a receptor may inhibit the binding of C5a to the C5a receptor.

A “partial agonist” of the C5a receptor elevates the activity of the C5areceptor above the basal activity level of the receptor in the absenceof C5a, but does not elevate the activity of the C5a receptor to thelevel brought about by saturating levels of the natural agonist, C5a.Partial agonist compounds may inhibit the binding of C5a to the C5areceptor. Partial agonists of the C5a receptor usually elevate theactive of the C5a receptor from 5% to 90% of the activity level broughtabout by saturated concentrations of the natural agonist, C5a.

A “C5a receptor modulatory amount” of a compound is an amount that issufficient to yield a plasma concentration of the compound (or itsactive metabolite, if a prodrug) high enough to detectably alter(modulate) C5a receptor activity and/or ligand binding, when thatconcentration is used in an in vitro assay. Suitable in vitro assaysinclude the standard in vitro C5 receptor-mediated chemotaxis assay(described in Example 46 herein); C5a receptor-mediated calciummobilization assay (described in Example 53 herein); and/or radioligandbinding assay such as the assay provided in Example 51.

A “therapeutically effective amount” of a compound is an amount that issufficient to result in a discernible patient benefit. For example, atherapeutically effective amount may reduce symptom severity orfrequency. Alternatively, or in addition, a therapeutically effectiveamount may improve patient outcome and/or prevent or delay disease orsymptom onset.

As used herein, a “pharmaceutically acceptable salt” is an acid or basesalt that is generally considered in the art to be suitable for use incontact with the tissues of human beings or animals without excessivetoxicity, irritation, allergic response, or other problem orcomplication. Such salts include mineral and organic acid salts of basicresidues such as amines, as well as alkali or organic salts of acidicresidues such as carboxylic acids. Specific pharmaceutical saltsinclude, but are not limited to, salts of acids such as hydrochloric,phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic,sulfanilic, formic, toluenesulfonic, methanesulfonic, benzene sulfonic,ethane disulfonic, 2-hydroxyethylsulfonic, nitric, benzoic,2-acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic,glutamic, ascorbic, pamoic, succinic, fumaric, maleic, propionic,hydroxymaleic, hydroiodic, phenylacetic, alkanoic such as acetic,HOOC₁—(CH₂)_(n)—COOH where n is 0-4 and the like. Similarly,pharmaceutically acceptable cations include, but are not limited tosodium, potassium, calcium, aluminum, lithium and ammonium. Those ofordinary skill in the art will recognize further pharmaceuticallyacceptable salts for the compounds provided herein, including thoselisted by Remington's Pharmaceutical Sciences, 17th ed., Mack PublishingCompany, Easton, Pa., p. 1418 (1985). Accordingly, the presentdisclosure should be construed to include all pharmaceuticallyacceptable salts of the compounds specifically recited. A wide varietyof synthetic procedures is available for the preparation ofpharmaceutically acceptable salts. In general, a pharmaceuticallyacceptable salt can be synthesized from a parent compound that containsa basic or acidic moiety by any conventional chemical method. Briefly,such salts can be prepared by reacting the free acid or base forms ofthese compounds with a stoichiometric amount of the appropriate base oracid in water, an organic solvent, or a mixture of the two; generally,nonaqueous media like ether, ethyl acetate, ethanol, isopropanol oracetonitrile are preferred.

A “prodrug” is a compound that may not fully satisfy the structuralrequirements of the compounds provided herein, but is modified in vivo,following administration to a patient, to produce a compound of FormulaI. For example, a prodrug may be an acylated derivative of a compound asprovided herein. Prodrugs include compounds wherein hydroxy, amine, orsulfhydryl groups are bonded to any group that, when administered to amammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydrylgroup, respectively. Examples of prodrugs include, but are not limitedto, acetate, formate, and benzoate derivatives of alcohol and aminefunctional groups within the compounds provided herein. Preferredprodrugs include acylated derivatives. Prodrugs may be prepared bymodifying functional groups present in the compounds in such a way thatthe modifications are cleaved to the parent compounds. Those of ordinaryskill in the art will recognize various synthetic methods that may beemployed to prepare prodrugs of the compounds provided herein.

A “patient” is any individual treated with a C5a modulator as providedherein. Patients include humans, as well as other animals such ascompanion animals (e.g., dogs and cats) and livestock. Patients may beexperiencing one or more symptoms of a condition responsive to C5anreceptor modulation, or may be free of such symptom(s) (i.e., treatmentmay be prophylactic).

C5A Receptor Modulators

As noted above, the present invention provides C5a receptor modulators(i.e., compounds that modulate C5a receptor-mediated signaltransduction; preferably compounds that also detectably bind to C5areceptor). C5a receptor modulators may be used to modulate C5a receptoractivity in a variety of contexts, including in the treatment ofpatients suffering from diseases or disorders responsive to C5a receptormodulation, such as autoimmune disorders and inflammatory conditions.C5a receptor modulators may also be used within a variety of in vitroassays (e.g., assays for receptor activity), as probes for detection andlocalization of C5a receptor and as standards in assays of ligandbinding and C5a receptor-mediated signal transduction.

C5a receptor modulators provided herein are aryl imidazoles and relatedcompounds of Formula I (as well as pharmaceutically acceptable salts andprodrugs thereof) that detectably alter, preferably decrease, C5areceptor activation and/or signal transduction activity at submicromolarconcentrations. Such an alteration in C5a receptor activity may bemeasured using a standard in vitro C5a receptor-mediated chemotaxisassay (Example 46), a C5a receptor-mediated calcium mobilization assay(Example 53) and/or a radioligand binding assay (Example 51). Thepresent invention is based, in part, on the discovery that smallmolecules of Formula I act as antagonists and/or inverse agonists of C5areceptors.

Thus, an embodiment of the invention is directed to compounds and thepharmaceutically acceptable salts of Formula I

wherein the ring system represented by

is a 5 membered heteroaryl ring system, in which x is 0, A is chosenfrom carbon and heteroatoms nitrogen, oxygen, and sulfur, and E and Gare independently carbon or nitrogen, provided that the 5 memberedheteroaryl ring system does not contain more than 3 heteroatoms or morethan 1 oxygen or sulfur atom, or a 6 membered heteroaryl ring system, inwhich x is 1, and A, B, E, and G are independently chosen from carbonand nitrogen, provided that the 6 membered heteroaryl ring system doesnot contain more than 3 mLrogen atoms.

R and R₁, in this embodiment are independently chosen from:

i) hydrogen, hydroxy, halogen, amino, cyano, nitro, —CHO, —CONH₂,C₁-C₆haloalkyl, C₁-C₆haloalkoxy,

ii) C₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆alkynyl, C₁-C₆alkanoyl, C₁-C₆alkoxy,C₃-C₇cycloalkyl, (C₃-C₇cycloalkyl)C₁-C₄alkyl, mono- anddi-C₁-C₆alkylamino, mono- and di-C₁-C₆alkylaminoC₁-C₆alkyl, mono- anddi-C₁-C₆alkylcarboxamide, C₁-C₆alkoxycarbonyl, —NHSO_(n)C₁-C₆alkyl,—SO_(n)(C₁-C₆alkyl), —(C₁-C₆alkyl)SO_(n)(C₁-C₆alkyl),—SO_(n)N(C₁-C₆alkyl) (C₁-C₆alkyl), and phenyl-SO_(n)—, each of which issubstituted with from 0 to 3 substituents independently chosen fromhydrogen, hydroxy, halogen, amino, cyano, oxo, C₁-C₄alkyl, C₁-C₄alkoxy,and C₁-C₂alkoxycarbonyl, and

iii) naphthyl, phenyl, phenylC₁-C₄carbhydryl, pyridyl, thiazolyl,pyrimidinyl, thienyl, pyridylC₁-C₄carbhydryl, thiazolylC₁-C₄carbhydryl,pyrimidinylC₁-C₄carbhydryl, and thienyl C₁-C₄carbhydryl, each of whichis substituted with from 0 to 3 substitutents independently chosen fromhydroxy, halogen, amino, cyano, nitro, —COOH, —CONH₂, —SO₂NH₂,C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₁-C₆alkyl, C₁-C₆alkoxy,1,3-dioxol-5-yl, C₁-C₆alkanoyl, C₁-C₆alkylsulfonyl, C₁-C₆alkylsulfinyl,C₁-C₆alkylthio, C₂-C₆alkanone; C₁-C₆alkanoyl; C₂-C₆alkyl ether; C₁-C₆alkanoyloxy; C₁-C₆alkoxycarbonyl, and C₁-C₆alkylcarboxamide.

R₂, when E is Nitrogen, is chosen from C₁-C₇alkyl, substituted with from0 to 3 substitutents independently chosen from hydroxy, halogen, amino,cyano, oxo, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₇ alkenyl, C₂-C₇ alkynyl,C₃-C₇cycloalkyl(C₁-C₄alkyl), benzyl, C₁-C₆haloalkyl, andC₁-C₆haloalkoxy.

R₂, when E is Carbon, is chosen from (i) hydrogen; halogen, and hydroxy;and (ii) C₁-C₇alkyl substituted with from 0 to 3 substitutentsindependently chosen from hydroxy, halogen, amino, cyano, oxo,C₁-C₄alkyl, C₁-C₄alkoxy, C₇-C₇alkenyl, C₂-C₇alkynyl, C₁-C₇alkoxy;C₁-C₇alkylamino; C₃-C₇cycloalkyl(C₁-C₄alkyl), benzyl, C₁-C₆haloalkyl,and C₁-C₆haloalkoxy.

When x is 0, R₁ and R₃ may be joined to form a cycloalkyl ring havingfrom 3 to 7 carbon atoms, which is substituted with from 0 to 4substituents independently chosen from hydroxy, halo-en, cyano,C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;

R₄ represents C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl,C₃-C₇ cycloalkenyl, (C₃-C₇cycloalkyl)C₁-C₄alkyl,(C₃-C₇cycloalkenyl)C₁-C₄alkyl, or hexahydro-1,3-benzodioxolylmethyl,each of which is substituted with from 0 to 3 substitutentsindependently chosen from hydrogen, hydroxy, halogen, amino, cyano,C₁-C₂alkyl, C₁-C₂alkoxy, and C₁-C₂alkoxycarbonyl; or

R₄ represents:

(i) arylC₀-C₄alkyl having 1 ring or 2 fused or pendant rings,

(ii) benzyl fused to a 5 to 7 membered saturated or partiallyunsaturated ring that (a) has 0, 1 or 2 ring atoms independently chosenfrom N, O and S, with remaining ring atoms being carbon, and (b) issubstituted with from 0 to 3 substituents independently chosen fromhalogen, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy,

(iii) heterocycloalkyl(C₀-C₄alkyl), or

(iv) heteroarylC₀-C₂alkyl, having 1 ring to 2 fused or pendant rings,from 5 to 7 members in each ring, and in at least one ring 1 to 3heteroatoms selected from N, O, and S,

wherein each of (i), (ii) (iii) and (iv) are substituted with from 0 to4 substituents independently chosen from hydroxy, halogen, amino, cyano,nitro, —COOH, —CONH₂, —SO₂NH₂, oxo, C₁-C₆haloalkyl, C₁-C₆haloalkoxy,C₁-C₆alkyl, C₁-C₆alkoxy, mono- and di-(C₁—CO₆)alkylamino, C₁-C₆alkanoyl,C₁-C₆sulfonate, C₁-C₆alkylsulfonyl, C₁-C₆alkylsulfinyl, C₁-C₆alkylthio,C₂-C₆alkanone, C₂-C₆alkyl ether; C1-C₆alkanoyloxy, C₁-C₆alkoxycarbonyl,and C₁-C₆alkylcarboxamide.

Ar₁ represents phenyl, quinolinyl, isoquinolinyl, phthalizinayl,benzimidazolyl, indanyl, tetralinyl, chromanyl, naphthyl, pyridyl,pyrimidinyl, pyridizinyl, pyrazinyl, pyrazolyl, imidazolyl, thiazolyl,isothiazolyl, pyrrolyl, oxazolyl, furanyl, or thienyl, each of which issubstituted with from 0 to 3 substituents independently chosen fromhydroxy, halogen, amino, C₁-C₆alkylamino, C₁-C₆alkylaminoC₁-C₆alkyl,cyano, nitro, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₁-C₆alkyl, and C₁-C₆alkoxy.

Ar₂ represents (v) C₃-C₇cycloalkyl, C₃-C₇cycloalkyl(C₁-C₄alkyl),C₃-C₇cycloalkenyl, C₃-C₇cycloalkenyl(C₁-C₄alkyl), orhexahydro-1,3-benzodioxolyl, (vi) aryl having 1 ring or 2 fused orpendant rings, (vii) phenyl fused to a 5 to 7 membered saturated orpartially unsaturated ring that (a) has 0, 1 or 2 ring atomsindependently chosen from N, O and S, with remaining ring atoms beingcarbon, and (b) is substituted with from 0 to 3 substituentsindependently chosen from halogen, C₁-C₄alkyl, C₁-C₄alkoxy,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, or (viii) heteroaryl, having 1ring, or 2 fused or pendant rings, from 5 to 7 members in each ring, andin at least one ring 1 to 3 heteroatoms selected from N, O, and S;wherein each of (v), (vi), (vii) and (viii) are substituted with from 0to 4 substituents independently chosen from hydroxy, halogen, amino,cyano, nitro, —COOH, —CONH₂, —SO₂NH₂, oxo, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₁-C₆alkyl, C₁-C₆alkoxy, mono- or di-C₁-C₆alkylamino,C₁-C₆alkanoyl, C₁-C₆alkylsulfonyl, C₁-C₆alkylsulfinyl, C₁-C₆alkylthio,C₂-C₆alkanone, C₂-C₆alkylether; C₁-C₆alkanoyloxy C₁-C₆alkoxycarbonyl,C₁-C₆alkylcarboxamide, C₂-C₆cycloalkylamino, andC₂-C₆cycloalkylamino(C₁-C₄alkyl).

The invention includes compounds and pharmaceutically acceptable saltsof Formula I wherein x is 0; A and C are carbon; E is nitrogen; and R₁and R₃ are not joined to form a cycloalkyl ring; i.e. compounds ofFormula II:

The invention also includes compounds and pharmaceutically acceptablesalts of Formula I wherein x is 0; A and E are carbon; G is nitrogen;and R₁ and R₃ are not joined to form a cycloalkyl ring, i.e. compoundsof Formula III

The invention further includes compounds and pharmaceutically acceptablesalts of Formula I wherein x is 0; F and G are carbon; A is nitrogen;and R₁ and R₃ are not joined to form a cycloalkyl ring, i.e. compoundsof Formula IV

The invention includes compounds and pharmaceutically acceptable saltsof Formula I wherein x is 0, G is carbon, A and E are nitrogen, i.e.compounds of Formula V

In yet another embodiment the invention includes compounds andpharmaceutically acceptable salts of Formula I wherein x is 0, A issulfur, G and E are carbon; and R₁ and R₃ are not joined to form acycloalkyl ring, i.e., compounds of Formula VI

In still another embodiment the invention includes compounds andpharmaceutically acceptable salts of Formula I wherein x is 0, A isoxygen, G and E are carbon; and R₁ and R₃ are not joined to form acycloalkyl ring, i.e. compounds of Formula VII

In another embodiment the invention includes compounds andpharmaceutically acceptable salts of Formula I wherein x is 1, and A, E,and G are carbon, and B is nitrogen, i.e. compounds of Formula VIII

In another embodiment the invention includes compounds andpharmaceutically acceptable salts of Formula I wherein x is 1, and A, B,E, and G are carbon, i.e. compounds of Formula IX

Another embodiment the invention includes compounds and pharmaceuticallyacceptable salts of Formula I wherein x is 1, and A is nitrogen and B E,and G are carbon, i.e. compounds of Formula X

Certain embodiments of the invention pertain to compounds and salts ofFormula I (or the subformulae thereof) in which z is 1; R₅ is hydrogen;and R₆ is hydrogen, methyl, or ethyl.

Other embodiments of the invention pertain to compounds and salts ofFormula I (or the subformulae thereof) in which z is 1; R₅ is hydrogen,R₆ is hydrogen, methyl, or ethyl; and Ar₁ is phenyl, pyrazolyl, orthienyl, each of which is substituted with 0 to 2 substituentsindependently chosen from halogen, hydroxy, C₁-C₂alkyl, C₁-C₂alkoxy,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

Still other embodiments of the invention pertain to compounds and saltsof Formula I (or the subformulae thereof) in which z is 1, R₅ and R₆ arehydrogen, and Ar¹ is unsubstituted phenyl or unsubstituted thienyl.

The Variable R₁:

The invention includes compounds and pharmaceutically acceptable saltsof the formulae and embodiments listed herein in which R₁ is phenylsubstituted with from 0 to 4 substituents independently chosen fromhydroxy, halogen, amino, cyano, nitro, —COOH, —CONH₂, —SO₂NH₂,C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₁-C₆alkyl, C₁-C₆alkoxy,1,3-dioxol-5-yl, C₁-C₆alkanoyl, C₁-C₆alkylsulfonyl, C₁-C₆alkylsulfinyl,C₁-C₆alkylthio, C₂-C₆alkanone; C₁-C₆alkanoyl; C₂-C₆alkyl ether; C₁-C₆alkanoyloxy, C₁-C₆alkoxycarbonyl, and C₁-C₆alkylcarboxamide.

In other embodiments the invention pertains to compounds andpharmaceutically acceptable salts of the formulae and embodiments listedherein in R₁ is phenyl substituted with from 0 to 2 substituentsindependently chosen from hydroxy, halogen, amino, cyano, nitro, —COOH,—CONH₂, —SO₂NH₂, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, C₁-C₂alkyl, andC₁-C₂alkoxy.

In other embodiments R₁ is unsubstituted phenyl.

The invention pertains to compounds and salts of the formulae describedherein in which

R₁ is thienyl or pyridyl, each of which is substituted with from 0 to 2substituents independently chosen from hydroxy, halogen, amino, cyano,nitro, —COOH, —CONH₂, —SO₂NH₂, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy,C₁-C₂alkyl, and C₁-C₂alkoxy.

In certain embodiments of the formulae described herein R₁ is hydrogen.

In other certain embodiments of the formulae described herein R₁ ishalogen, C₁-C₄alkyl, C₁-C₄alkoxy, cyano, trifluoromethyl,pentafluoroethyl, C₁-C₂alkylaminoC₁-C₂alkyl, hydroxymethyl, orhydroxyethyl.

In still other embodiments of the formulae described herein R₁ ishalogen.

The invention further includes compounds and salts of the formulaedescribed herein

-   R₁ is trifluoromethyl, pentafluoroethyl, difluoromethyl,    trifluoromethoxy, or difluoromethoxy.-   The Variable R₂:

The invention includes compounds and salts Formula I and the subformulaethereof in which R₂ is propyl, butyl, pentyl, 3-methylbutyl,methoxyethyl.

-   The Variable R₃:

The invention pertains to compounds and salts Formula I and thesubformulae thereof in which

-   R₃ is hydrogen.

The invention further pertains to compounds and salts Formula I and thesubformulae thereof wherein R₃ is C₁-C₅ alkyl.

The invention includes still other compounds and salts Formula I and thesubformulae thereof in which

-   R₄ represents C₁-C₆alkyl.-   The Variable R₄:

The invention pertains to compounds and salts Formula I and thesubformulae thereof in which

R₄ represents C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇cycloalkyl, C₃-C₇ cycloalkenyl, (C₃-C₇cycloalkyl)C₁-C₄alkyl,(C₃-C₇cycloalkenyl)C₁-C₄,alkyl, or hexahydro-1,3-benzodioxolylmethyl,each of which is substituted with from 0 to 3 substituents independentlychosen from hydroxy, halogen, amino, cyano, C₁-C₂alkyl, C₁-C₂alkoxy, andC₁-C₂alkoxycarbonyl.

The includes compounds and salts Formula I and the subformulae thereofin which R₄ represents C₁-C₆alkyl, C₃-C₇ cycloalkenyl,(C₃-C₇cycloalkyl)C₁-C₄alkyl, (C₃-C₇cycloalkenyl) C₁-C₄alkyl, orhexahydro-1,3-benzodioxolylmethyl.

The invention also pertains to compounds and salts Formula I and thesubformulae thereof in which R₄ represents cyclopentyl, cyclohexyl,cyclohexenyl, cyclohexylmethyl, cyclohexenylmethyl, cyclohexenyl, orhexahydro-1,3-benzodioxolylmethyl.

The invention also includes compounds and salts Formula I and thesubformulae thereof in which R₄ represents cyclohexylmethyl.

Further included in the invention are compounds and salts Formula I andthe subformulae thereof in which R₄

-   R₄ represents

(i) aryl or aryl(C₁-C₂)alkyl having 1 ring or 2 fused or pendant rings,

(ii) benzyl fused to a 5- to 7-membered saturated or partiallyunsaturated ring, that (a) has 0, 1 or 2 ring atoms independently chosenfrom N, O and S, with remaining ring atoms being carbon, and (b) issubstituted with from 0 to 3 substituents independently chosen fromhalogen, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;

(iii saturated or partially unsaturated heterocyclic(C₀-C₁alkyl) having1 ring or 2 fused or pendant rings, from 5 to 7 members in each ring,and in at least one ring 1 to 3 heteroatoms selected from N, O, and S;or

(iv) heteroaryl or heteroaryl(C₀-C₂alkyl), having 1 ring or 2 fused orpendant rings, from 5 to 7 members in each ring, and in at least onering 1 to 3 heteroatoms selected from,N, O, and S, wherein each of (i),(ii), (iii), and (iv) are substituted with from 0 to 4 substituentsindependently chosen from hydroxy, halogen, amino, cyano, nitro, —COOH,—CONH₂, —SO₂NH₂, oxo, C₁-C₆ haloalkyl, C₁-C₆-haloalkoxy, C₁-C₆alkyl,C₁-C₆alkoxy, C₁-C₆alkanoyl, C₁-C₆sulfonate, C₁-C₆alkylsulfonyl,C₁-C₆alkylsulfinyl, C₁-C₆alkylthio, C₁-C₆alkanone, C₂-C₆alkyl ether,C₁-C₆ alkanoyloxy, C₁-C₆alkoxycarbonyl, and C₁-C₆alkylcarboxamide.

The invention pertains to compounds and salts Formula I and thesubformulae thereof in which R₄ is benzyl substituted with from 0 to 4substituents independently chosen from hydroxy, halogen, amino, cyano,nitro, —COOH, —CONH₂, —SO₂NH₂, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, mono-and di-(C₁-C₆)alkylamino, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆alkanoylC₁-C₆alkylsulfonate, C₁-C₆alkylsulfonyl, C₁-C₆alkylsulfinyl,C₁-C₆alkylthio, C₂-C₆alkanone, C₂-C₆alkyl ether, C₁-C₆ alkanoyloxy,C₁-C₆alkoxycarbonyl, and C₁-C₆ alkylcarboxamide.

Also included in the invention are compounds and salts Formula I and thesubformulae thereof in which R₄ represents benzyl substituted with from0 to 3 substituents independently chosen from hydroxy, halogen, amino,cyano, nitro, —COOH, —CONH₂, —SO₂NH₂, —SH, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, mono- and di-(C₁-C₂)alkylamino, C₁-C₄alkoxy, C₁-C₂alkanoyl,C₁-C₂alkylsulfonate, C₁-C₂alkylsulfonyl, C₁-C₂alkylsulfinyl,C₁-C₂alkylthio, C₂-C₃alkanone, C₂-C₆alkylether, C₁-C₄ alkanoyloxy,C₁-C₄alkoxycarbonyl, and C₁-C₂alkylcarboxamide.

Included in the invention are compounds and salts Formula I and thesubformulae thereof in which R₄ represents benzyl substituted with from0 to 3 substituents independently chosen from hydroxy, halogen, amino,cyano, nitro, —COOH, —CONH₂, —SO₂NH₂, pentafluoroethyl,tetrafluoromethyl, trifluoromethyl, difluoromethyl, pentafluoroethoxy,tetrafluoroethoxy, trifluoromethoxy, difluoromethoxy, C₁-C₂alkyl,C₁-C₄alkoxy, C₁-C₂alkanoyl, C₁-C₂alkyl sulfonate, C₁-C₂alkylsulfonyl,C₁-C₂alkylsulfinyl, C₁-C₂alkylthio, C₂-C₃alkanone; C₁-C₄ alkanoyloxy,ethoxycarbonyl, methoxycarbonyl, and —NH₂(C═O)CH₃.

The invention also pertains to compounds and salts Formula I and thesubformulae thereof in which R₄ represents pyridylmethyl,pyrimidylmethyl, thienylmethyl, napthylmethyl, indolylmethyl,benzoxadialolylmethyl, benzoxazolylmethyl, quinazolinylmethyl,benzothiazolylmethyl, or benzimidazolylmethyl, optionally substitutedwith from 0 to 2 substituents independently chosen from hydroxy,halogen, amino, cyano, C₁-C₂ alkyl, C₁-C₂alkoxy, C₁-C₂ haloalkyl,C₁-C₂haloalkoxy, and mono- and di-(C₁-C₂)alkylamino.

In certain embodiments the invention pertains to compounds and saltsFormula I and the subformulae thereof in which R₄ representsbenzoxadiazol-5-ylmethyl.

The invention includes compounds and salts Formula I and the subformulaethereof in which R₄ represents benzyl fused to a 5- to 7-memberedsaturated or partially unsaturated ring that (a) has 0, 1, or 2 ringatoms independently chosen from N, O and S, with remaining ring atomsbeing carbon, and (b) is substituted with from 0 to 3 substituentsindependently chosen from hydroxy, halogen, amino, cyano, nitro, —COOH,—CONH₂, —SO₂NH₂ oxo, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆alkyl,C₁-C₆alkoxy, mono- and di-(C₁-C₆)alkylamino, C₁-C₆alkanoyl,C₁-C₆sulfonate, C₁-C₆alkylsulfonyl, C₁-C₆alkylsulfinyl, C₁-C₆alkylthio,C₂-C₆alkanone, C₂-C₆alkyl ether; C₁-C₆ alkanoyloxy; C₁-C₆alkoxycarbonyl,and C₁-C₆alkylcarboxamide.

In yet other embodiments the invention includes compounds and salts ofFormula

I in which

-   R₄ represents 1,3-benzodioxol-5-ylmethyl,    2,3-dihydro-1-benzofuran-6-ylmethyl,    2,3-dihydro-1-benzofuran-5-ylmethyl,    2,3-dihydro-1,4-benzodioxin-6-ylmethyl, chroman-6-ylmethyl,    chroman-7-ylmethyl, 1,3-benzothiazolylmethyl,    2,3-dihydroindol-5-ylmethyl, each of which is substituted from 0 to    2 substituents independently selected from hydroxy, halogen, amino,    cyano, oxo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₂alkyl,    C₁-C₂alkoxy, mono- and di-(C₁-C₂)alkylamino.

In certain embodiments R₄ represents 1,3-benzodioxol-5-ylmethyl.

In still other embodiments R₄ is a saturated or partially unsaturatedheterocyclic(C₀-C₄alkyl) group having from 4 to 7 ring members, 1 or 2of which ring members are N, S or O, with remaining ring members beingcarbon, substituted with from 0 to 4 substituents independently chosenfrom hydroxy, halogen, amino, cyano, nitro, —COOH, —CONH₂, —SO₂NH₂, oxo,C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₁-C₆alkyl, C₁-C₆alkoxy, mono- anddi-(C₁-C₆)alkylamino, C₁-C₆alkanoyl, C₁-C₆sulfonate, C₁-C₆alkylsulfonyl,C₁-C₆alkylsulfinyl, C₁-C₆alkylthio, C₂-C₆alkanone, C₂-C₆alkylether,C₁-C₆alkanoyloxy, C₁-C₆alkoxycarbonyl, and C₁-C₆alkylcarboxamide.

The invention also pertains to compounds and salts of Formula I and thesubformulae thereof in which R₄ is morpholinyl(C₀-C₄alkyl),azetidinyl(C₀-C₄alkyl), piperazinyl(C₀-C₄alkyl),piperidinyl(C₀-C₄alkyl), pyrrolidinyl(C₀-C₄alkyl),tetrahydropyranyl(C₀-C₄alkyl), or tetrahydropyridinyl(C₀-C₄alkyl), eachof which is substituted by from 0 to 2 substituents independentlyselected from hydroxy, halogen, amino, cyano, oxo, C₁-C₂ alkyl,C₁-C₂alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, mono anddi-(C₁-C₂)alkylamino.

Also included in the invention are compounds and salts of Formula I andthe subformulae thereof in which: R₄ is a heteroaryl orheteroaryl(C₁-C₂alkyl) group, having 1 ring or 2 fused or pendant rings,from 5 to 7 members in each ring, and in at least one ring 1 to 3heteroatoms selected from N, O, and S, substituted with from 0 to 4substituents independently chosen from hydroxy, halogen, amino, cyano,nitro, —COOH, —CONH₂, —SO₂NH₂, oxo, C₁-C₆ alkyl, C₁-C₆alkoxy,C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₁-C₆alkanoyl, C₁-C₆sulfonate,C₁-C₆alkylsulfonyl, C₁-C₆alkylsulfinyl, C₁-C₆alkylthio, C₁-C₆alkanone,C₂-C₆alkyl ether, C₁-C₆alkanoyloxy, C₁-C₆alkoxycarbonyl, andC₁-C₆alkylcarboxamide.

The invention pertains to compounds and salts of Formula I and thesubformulae

thereof in which

-   R₄ is pyridylmethyl, pyrimidinylmethyl, thienylmethyl,    naphthylmethyl, indolylmethyl, benzoxadiazolylmethyl,    benzoxazolylmethyl, quinazolinylmethyl, or benzimidazolylmethyl,    each of which is substituted with from 0 to 2 substituents    independently chosen from hydroxy, halogen, amino, cyano,    C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₂alkyl, and C₁-C₂alkoxy,-   The Variable Ar₂

In other embodiments the invention pertains to compounds and salts ofFormula I and the subformulae thereof in which Ar₂ representsC₃-C₇cycloalkyl, C₃-C₇cycloalkenyl, (C₃-C₇cycloalkyl)C₁-C₄alkyl,(C₃-C₇cycloalkenyl)C₁-C₄alkyl, or hexahydro 1,3-benzodioxolyl, each ofwhich is substituted with from 0 to 3 substituents independently chosenfrom hydroxy, halogen, amino, cyano, C₁-C₂alkyl, C₁-C₂alkoxy, andC₁-C₂alkoxycarbonyl.

The invention includes compounds and salts of Formula I and thesubformulae

thereof in which

-   Ar₂ represents

(i) C₁-C₆cycloalkyl, C₃-C₇ cycloalkenyl, or hexahydro-1,3-benzodioxolyl;or

(ii) cyclopentyl, cyclohexyl, cyclohexenyl, orhexahydro-1,3-benzodioxolyl; or

(iii) phenyl substituted with from 0 to 4 substituents independentlychosen from hydroxy, halogen, amino, cyano, nitro, —COOH, —CONH₂,—SO₂NH₂, oxo, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ alkyl,C₁-C₆alkoxy, mono- and di-C₁-C₆alkylamino, C₁-C₆alkanoyl,C₁-C₆alkylsulfonyl, C₁-C₆alkylsulfinyl, C₁-C₆alkylthio, C₂-C₆alkanone,C₂-C₆alkylether; C₁-C₆alkanoyloxy C₁-C₆alkoxycarbonyl,C₁-C₆alkylcarboxamide, C₂-C₆cycloalkylamino, andC₂-C₆cycloalkylamino(C₃-C₄alkyl); or

(iv) phenyl substituted with from 0 to 3 substituents independentlychosen from hydroxy, halogen, amino, cyano, nitro, —COOH, —CONH₂,—SO₂NH₂, —SH, C₁-C₂haloalkyl, C₁-C₂ haloalkoxy, C₁-C₂alkyl, C₁-C₄alkoxy,C₁-C₂alkanoyl, mono- and di-C₁-C₂alkylamino, C₁-C₂alkylsulfonate,C₁-C₂alkylsulfonyl, C₁-C₂alkylsulfinyl, C₁-C₂alkylthio, C₂-C₃alkanone,C₂-C₆alkyl ether, C₁-C₄ alkanoyloxy, C₁-C₄alkoxycarbonyl,C₁-C₂alkylcarboxamide, and C₂-C₆cycloalkylamino.

In other embodiments the invention pertains to compounds and salts ofFormula I and the subformulae thereof in which Ar₂ represents phenylsubstituted with from 0 to 3 substituents independently chosen fromhydroxy, halogen, amino, cyano, nitro, —COOH, —CONH₂, —SO₂NH₂,pentafluoroethyl, tetrafluoromethyl, trifluoromethyl, difluoromethyl,pentafluoroethoxy, tetrafluoroethoxy, trifluoromethoxy, difluoromethoxy,C₁-C₂ alkyl, C₁-C₄alkoxy, C₁-C₂alkanoyl, mono- and di-C₁-C₂alkylamino,C₁-C₂alkylsulfonate, C₁-C₂alkylsulfonyl, C₁-C₂alkylsulfinyl,C₁-C₂alkylthio, C₂-C₃alkanone; C₁-C₄ alkanoyloxy, ethoxycarbonyl,methoxycarbonyl, —NH₂(C═O)CH₃, and C₁-C₆cycloalkylamino.

The invention also includes compounds and salts of Formula I and thesubformulae thereof in which Ar₂ represents pyridyl, pyrimidyl, thienyl,naphthyl, indolyl, benzoxadiazolyl, benzoxazolyl, quinazolinyl, orbenzimidazolyl substituted with from 0 to 2 substituents independentlychosen from hydroxy, halogen, amino, cyano, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₂ alkyl, C₁-C₂alkoxy, mono- and di-C₁-C₂alkylamino,and C₂-C₆cycloalkylamino.

In other embodiments the invention pertains to compounds and salts ofFormula I and the subformulae thereof in which Ar₂ representsbenzoxadiazol-5-yl.

Further included in the invention are compounds and salts of Formula Iand the subformulae thereof in which Ar₂ represents

-   (i) phenyl fused to a 5- to 7-membered saturated or partially    unsaturated ring that (a) has 0, 1, or 2 ring atoms independently    chosen from N, O and S, with remaining ring atoms being carbon,    and (b) is substituted with from 0 to 3 substituents independently    chosen from halogen, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl, and    C₁-C₂haloalkoxy-   (ii) a heteroaryl or heteroaryl(C₁-C₂alkyl) group, having 1 ring or    2 fused or pendant rings, from 5 to 7 members in each ring, and in    at least one ring 1 to 3 heteroatoms selected from N, O, and S,    wherein each of (i) and (ii) are substituted with from 0 to 4    substituents independently chosen from hydroxy, halogen, amino,    cyano, nitro, —COOH, —CONH₂, —SO₂NH₂, oxo, C₁-C₆haloalkyl,    C₁-C₆haloalkoxy, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆alkanoyl,    C₁-C₆sulfonate, C₁-C₆alkylsulfonyl, C₁-C₆alkylsulfinyl,    C₁-C₆alkylthio, C₂-C₆alkanone, C₂-C₆alkyl ether, C₁-C₆ alkanoyloxy;    C₁-C₆alkoxycarbonyl, and C₁-C₆alkylcarboxamide.

The invention includes compounds and salts of Formula I and thesubformulae thereof in which Ar₂ represents 1,3-benzodioxol-5-yl,2,3-dihydro-1-benzofuran-6-yl, 2,3-dihydro-1-benzofuran-5-yl,2,3-dihydro-1,4-benzodioxin-6-yl, chroman-6-yl, chroman-7-yl,1,3-benzothiazolyl, or 2,3-dihydroindol-5-yl, each of which issubstituted with from 0 to 2 substituents independently selected fromhydroxy, halogen, amino, cyano, oxo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₂ alkyl, and C₁-C₂alkoxy.

In other embodiments the invention pertains compounds and salts ofFormula I and the subformulae thereof in which Ar₂ represents Ar₂represents 1,3-benzodioxol-5-yl.

Additional Embodiments

In another embodiment the invention includes compounds and salts ofFormula I in which R₁ and R₃ are joined to form a cycloalkyl ringsubstituted with from 0 to 4 substituents independently chosen fromhydroxy, halogen, cyano, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂haloalkyl, andC₁-C₂haloalkoxy, e.g. compounds of Formula XI:

The invention includes compounds and salts of Formula XI are thosewherein z is 1, R₅ is hydrogen, and R₆ is hydrogen or methyl.

The invention also includes compounds and salts of Formula XI are thosewherein a is 1 and XI is represents from 0 to 2 substituents chosen from1 or 2 groups independently chosen from hydroxy, halogen, C₁-C₂alkyl,and C₁-C₂alkoxy.

The invention further includes compounds and salts of Formula XI alsoinclude those wherein a is 2 and XI is represents from 0 to 2 optionalsubstituents chosen from 1 or 2 groups independently chosen fromhydroxy, halogen, C₁-C₂alkyl, and C₁-C₂alkoxy.

The invention pertains to compounds and salts of Formula XI in which R₂is propyl, butyl, pentyl and 3-methylbutyl; butyl is preferred.

In other embodiments the invention pertains to compounds and salts ofFormula XI is phenyl in which Ar₁ is optionally substituted with from 1to 3 groups independently chosen from hydroxy, halogen, amino, cyano,nitro, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

Values of R₄ for compounds and salts of Formula XI include C₃-C₅ alkyl.

-   -   Other values of R₄ for compounds and salts of Formula XI include        benzyl optionally substituted with from 1 to 3 groups        independently chosen from hydroxy, halogen, amino, cyano, nitro,        C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

Values of Ar₂ for compounds and salts of Formula XI include phenyloptionally substituted with from 1 to 3 groups independently chosen fromhydroxy, halogen, amino, cyano, nitro, C₁-C₂haloalkyl, C₁-C₂alkylamino,C₁-C₂haloalkoxy, and C₂-C₆cycloalkylamino.

Additional embodiments of the invention include compounds of FormulaXII-Formula XXIX as follows:

and the pharmaceutically acceptable salts thereof wherein:

R₂ is C₃-C₅ alkyl. Preferably R₂ is butyl or methoxyethyl

R₃ is hydrogen or methyl.

R₄ in Formula XIV, Formula XVII, and Formula XVIX represents a straightor branched chain C₃-C₆ alkyl group. Preferably R₄ is butyl, isobutyl,neopentyl, or cyclohexylmethyl.

R₅ is hydrogen or methyl, preferably hydrogen.

R₇ represents 0 to 3 groups independently chosen from hydroxy, cyano,halogen, methyl, ethyl, methoxy, and ethoxy. Preferably R₇ is absent ormethyl. In certain compounds of the invention the phenyl group shown inFormula XII-XXIX as substituted with R₇ (corresponding to Ar₁ in FormulaI, is instead a thienyl or pyrazolyl group, each of which is optionallysubstituted by R₇). In other compounds of the invention this phenylgroup is a 2,6-dimethylphenyl or a 2,6-diethylphenyl.

R₈ represents 0 to 3 groups independently chosen from halogen, hydroxy,nitro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl,trifluoromethoxy, difluoromethoxy, —CONH₂, —OC(═O)CH₃, —COOH,methylthio, ethylthio, and —SO₂CH₃. In certain preferred compounds ofthe invention the phenyl group shown in Formula XII-XX and FormulaXXII-XXIX as substituted with R₈ (corresponding to R₁ in Formula I forthe imidazole compounds and R for the pyridizine compounds, is instead athienyl group, which is optionally substituted by R₈).

R₉ and R₁₀ may occur at any position on the piperonyl or benzodioxanylgroup available for substitution and independently represent 0 to 3chosen from halogen, methyl, and methoxy. Preferably R₉ and R₁₀ areabsent.

R₁₁ and R₁₂ independently represent 0 to 3 groups chosen from halogen,hydroxy, nitro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl,difluoromethyl, pentafluoroethyl, —CF₂CHF₂, trifluoromethoxy,difluoromethoxy, pentafluoroethoxy, —OCF₂CHF₂, —CONH₂, —C(═O)OCH₃,—OC(═O)CH₃, —COOH, methylthio, ethylthio, —SO₂NH₂, and —SO₂CH₃.Compounds in which R₁₁ or R₁₂ represents a single meta or parasubstituent are particularly embodied.

R₁₃ represents 0 to 3 groups independently chosen from halogen, methyl,and C₁-C₄alkoxy. R₁₃ is absent in certain embodiments of the invention.

R₁₄ may occur at any position on the indole, indazole, or benzisoxazolegroup available for substitution and represents 0 to 3 groupsindependently chosen from halogen, methyl, cyano, and amino. R₁₄ isabsent in certain embodiments of the invention.

Additionally the invention pertains to compounds of Formulae X-FormulaXXXVIII:

As well as compound of Formula XXXVIII-a

in Ar₂ is chosen from:

and the pharmaceutically acceptable salts thereof, wherein:

R₁ is selected from halogen, cyano, nitro, amino, —CHO, C₁-C₄alkyl,C₁-C₄alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₂alkoxyC₁-C₂alkyl,mono- or di-C₁-C₂)alkylaminoC₁-C₂alkyl, C₁-C₂alkoxycarbonyl,C₁-C₂alkylthio, C₁-C₂alkylsulfinyl, and C₁-C₂alkylsulfonyl.

Values of R₁ include halo-en, particularly fluoro, chloro, and bromo.Other preferred values of R₁ for compounds and salts of FormulaXXX-XXXVIII include cyano, C₁-C₂₁haloalkyl, C₁-C₂haloalkoxy,particularly, trifluoromethyl, difluoromethyl, trifluoromethoxy, anddifluoromethoxy.

R₂ is C₃-C₅ alkyl. Preferably R₂ is butyl or methoxyethyl

R₃ is hydrogen or methyl.

R₄ is C₃-C₆alkyl. In certain embodiments R₄ is butyl, isobutyl,neopentyl, and cyclohexylmethyl.

R₅ is hydrogen or methyl, preferably hydrogen.

R₇ represents 0 to 3 groups independently chosen from hydroxy, cyano,halogen, methyl, ethyl, methoxy, and ethoxy. Preferably R₇ is absent ormethyl. In certain preferred compounds of the invention the phenyl groupshown in Formula XXX-XXXVIII as substituted with R₇ (corresponding toAr₁ in Formula I, is instead a thienyl or pyrazolyl group, each of whichis optionally substituted by R₇). In other embodiments this phenyl groupis a 2,6-dimethylphenyl or 2,6-diethylphenyl

R₉ and R₁₀ may occur at any position on the piperonyl or benzodioxanylgroup available for substitution and independently represent 0 to 3chosen from halogen, methyl, and methoxy. Preferably R₉ and R₁₀ areabsent.

R₁₁ and R₁₂ independently represent 0 to 3 groups chosen from halo-en,hydroxy, nitro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl,difluoromethyl, pentafluoroethyl, —CF₂CHF₂, trifluoromethoxy,difluoromethoxy, pentafluoroethoxy, —OCF₂CHF₂, —CONH₂, —C(═O)OCH₃,—OC(═O)CH₃, —COOH, methylthio, ethylthio, —SO₂NH₂, and SO₂CH₃. Compoundsin which R₁₁ or R₁₂ represents a single meta or para substituent areembodied.

The invention is directed to compounds of Formulae XXXIX-Formula XLII

and the pharmaceutically acceptable salts thereof, wherein:

R₁ (or R) is selected from halogen, cyano, nitro, amino, —CHO,C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₂alkoxyC₁-C₂alkyl, mono- or di-(C₁-C₂)alkylaminoC₁-C₂alkyl,C₁-C₂alkoxycarbonyl, C₁-C₂alkylthio, C₁-C₂alkylsulfinyl, andC₁-C₂alkylsulfonyl.

Values of R₁ and R include halogen, particularly fluoro, chloro, andbromo. Other preferred values of R₁ and R for compounds and salts ofFormula XXII-XXIV include cyano, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,particularly, trifluoromethyl, difluoromethyl, trifluoromethoxy, anddifluoromethoxy.

R₂ is C₃-C₅ alkyl. Preferably R₂ is butyl or methoxybutyl

R₃ is C₁-C₆ alkyl.

R₄ represents C₁-C₆alkyl, C₃-C₇ cycloalkenyl, (C₃-C₇cycloalkyl)C₁-C₄alkyl, (C₃-C₇cycloalkenyl) C₁-C₄alkyl. Preferably R₄ is C₁-C₅alkyl.

R₅ is C₁-C₆alkyl, preferably methyl.

R₇ represents 0 to 3 groups independently chosen from hydroxy, cyano,halogen, methyl, ethyl, methoxy, and ethoxy. Preferably R₇ is absent ormethyl. In certain preferred compounds of the invention the phenyl groupshown in Formula I-XLII as substituted with R₇ (corresponding to Ar₁ inFormula I, is instead a thienyl or pyrazolyl group, each of which isoptionally substituted by R₇).

R₉ and R₁₀ may occur at any position on the piperonyl or otherheterocyclic group available for substitution and independentlyrepresent 0 to 3 chosen from halogen, methyl, and methoxy. Preferably R₉and R₁₀ are absent.

R₁₁ represents 0 to 3 groups chosen from halogen, hydroxy, nitro,methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl,pentafluoroethyl, —CF₂CHF₂, trifluoromethoxy, difluoromethoxy,pentafluoroethoxy, —OCF₂CHF₂, —CONH₂, —C(═O)OCH₃, —OC(═O)CH₃, —COOH,methylthio, ethylthio, —SO₂NH₂, and —SO₂CH₃. Compounds in which R₁₁ ofR₁₂ represents a single meta or para substituent are particularlypreferred.

Representative compounds of Formula I provided herein include, but arenot limited to those specifically described in Examples 1-41. It will beapparent that the specific compounds recited therein are representativeonly, and are not intended to limit the scope of the present invention.Further, as noted above, all compounds of the present invention may bepresent as a hydrate, free base or a pharmaceutically acceptable acidaddition salt.

Certain substituted compounds Formulae I (and the subformula thereof)have one or more stereogenic centers. In certain embodiment thereof,such compounds may be enantiomers, and may have an enantiomeric excessof at least 55%. Within further embodiments thereof, such compounds havean enantiomeric excess of at least 60%, 70%, 80%, 85%, 90%, 95%, 98%, or99%. Certain compounds having one or more stereogenic centers have aenantiomeric excess of at least 99%.

Certain compounds of Formulae I (and the subformulae thereof) have twoor more stereogenic centers. In certain embodiments thereof, suchcompounds have a diastereomeric excess of at least 55%. In otherembodiments thereof such compounds have a diastereomeric excess of 60%,70%, 80%, 85%, 90%, 95%, or 98%. Certain compounds having two of morestereogenic centers have a diastereomeric excess of at least 99%.

Aryl imidazoles and related compounds provided herein detectably alter(modulate) C5a receptor activity and/or ligand binding, as determinedusing a standard in vitro C5 receptor-mediated chemotaxis assay(described in Example 46), radioligand binding (described in Example51), or C5a receptor-mediated calcium mobilization assay (described inExample 53). Preferred compounds exhibit an IC₅₀ of about 500 nM or lessin such a standard C5a receptor-mediated chemotaxis, radioligandbinding, and/or calcium mobilization assay, more preferably an IC₅₀ ofabout 250 nM or less in such an assay, still more preferably an IC₅₀ ofabout 200, 150, 100, 50, 25, 10, or 5 nM or less in such an assay.

Initial characterization of compounds can be conveniently carried outusing a C5a receptor binding assay or functional assay, such as setforth in the Examples, and may be expedited by applying such assays in ahigh throughput screening setting. Additional assays suitable fordetermining the effects of small molecule compounds on C5a receptorbinding and receptor modulatory activity, as well as assays suitable formeasuring their effects on C5a-induced neutropenia in vivo, can be foundin the published literature, for example in U.S. Pat. No. 5,807,824,which is incorporated herein by reference for its disclosure in thisregard in Examples 6-9, columns 19-23, as well as for its discussion ofcomplement and inflammation at columns 1-2. Those of skill in the artwill recognize that such assays can be readily adapted to the use ofcells or animals of different species as deemed appropriate.

In certain embodiments, preferred compounds have favorablepharmacological properties, including oral bioavailability (such that asub-lethal or preferably a pharmaceutically acceptable oral dose,preferably less than 2 grams, more preferably of less than or equal toone grain, can provide a detectable in vivo effect such as a reductionof C5a-induced neutropenia), ability to inhibit leukocyte chemotaxis atnanomolar concentrations and preferably at sub-nanomolar concentrations,low toxicity (a preferred compound is nontoxic when a C5areceptor-modulatory amount is administered to a subject), minimal sideeffects (a preferred compound produces side effects comparable toplacebo when a C5a receptor-modulatory amount of the compound isadministered to a subject), low serum protein binding, and a suitable invitro and in vivo half-life (a preferred compound exhibits an in vitrohalf-life that is equal to an in vivo half-life allowing for Q.I.D.dosing, preferably T.T.D. dosing, more preferably B.I.D. dosing, andmost preferably once-a-day dosing). Distribution in the body to sites ofcomplement activity is also desirable (e.g., compounds used to treat CNSdisorders will preferably penetrate the blood brain barer, while lowbrain levels of compounds used to treat periphereal disorders aretypically preferred).

Routine assays that are well known in the art may be used to assessthese properties, and identify superior compounds for a particular use.For example, assays used to predict bioavailability include transportacross human intestinal cell monolayers, such as Caco-2 cell monolayers.Penetration of the blood brain barrier of a compound in humans may bepredicted from the brain levels of the compound in laboratory animalsgiven the compound (e.g., intravenously). Serum protein binding may bepredicted from albumin binding assays, such as those described byOravcová, et al. (1996) Journal of Chromatography B 677:1-27. Compoundhalf-life is inversely proportional to the frequency of dosage of acompound required to achieve an effective amount. In vitro half-lives ofcompounds may be predicted from assays of microsomal half-life asdescribed by Kuhnz and Gieschen (1998) Drug Metabolism and Disposition126: 1120-27.

Toxicity and side effects may be assessed using any standard method. Ingeneral, the term “nontoxic” as used herein shall be understood in arelative sense and is intended to refer to any substance that has beenapproved by the United States Food and Drug Administration (“FDA”) foradministration to mammals (preferably humans) or, in keeping withestablished criteria, is susceptible to approval by the FDA foradministration to mammals (preferably humans). Toxicity may be alsoevaluated using the assay detecting an effect on cellular ATPproduction. Other assays that may be used include bacterial reversemutation assays, such as an Ames test, as well as standardteratogenicity and tumorogenicity assays. Preferably, administration ofcompounds provided herein at certain doses (i.e., doses yieldingeffective in vivo concentrations) does not result in prolongation ofheart QT intervals (i.e., as determined by electrocardiography in guineapigs, minipigs or dogs). When administered daily for five or preferablyten days, such doses also do not cause liver enlargement resulting in anincrease of liver to body weight ratio of more than 100%, preferably notmore than 75%, and more preferably not more than 50% over matchedcontrols in laboratory rodents (e.g., mice or rats). Such doses alsopreferably do not cause liver enlargement resulting in an increase ofliver to body weight ratio of more than 50%, preferably not more than25%, and more preferably not more than 10% over matched untreatedcontrols in dogs or other non-rodent mammals.

Certain preferred compounds also do not promote substantial release ofliver enzymes (e.g., ALT, LDH or AST) from hepatocytes in vivo.Preferably the above doses do not elevate serum levels of such enzymesby more than 100%, preferably not by more than 75%, and more preferablynot by more than 50% over matched untreated controls in vivo inlaboratory rodents. Similarly, concentrations (in culture media or othersuch solutions that are contacted and incubated with cells in vitro)equivalent to two-fold, preferably five-fold, and most preferablyten-fold the minimum in vivo therapeutic concentration do not causedetectable release of any of such liver enzymes from hepatocytes invitro into culture medium above baseline levels seen in media fromuntreated cells.

In certain embodiments, preferred compounds exert theirreceptor-modulatory effects with high specificity. This means that theyonly bind to, activate, or inhibit the activity of certain receptorsother than C5a receptors with affinity constants of greater than 100nanomolar, preferably greater than 1 micromolar, more preferably greaterthan 4 micromolar. The invention also includes highly specific C5areceptor modulatory compounds that exhibit 200-fold greater affinity forthe C5a receptor that for other cellular receptors. Such receptorsinclude neurotransmitter receptors such as alpha or beta-adrenergicreceptors, muscarinic receptors (particularly m1, m2 or m3 receptors),dopamine receptors, and metabotropic glutamate receptors; as well ashistamine receptors and cytokine receptors (e.g., interleukin receptors,particularly IL-8 receptors). Such receptors may also include GABA_(A)receptors, bioactive peptide receptors (other than C5a receptors and C3areceptors, including NPY or VIP receptors), neurokinin receptors,bradykinin receptors, and hormone receptors (e.g., CRF receptors,thyrotropin releasing hormone receptors or melanin-concentrating hormonereceptors). Compounds that act with high specificity generally exhibitfewer undesirable side effects.

Within certain embodiments, modulators provided herein do not binddetectably to receptors that do not mediate inflammatory responses, suchas GABA receptors, MCH receptors, NPY receptors, dopamine receptors,serotonin receptors and VR1 receptors, with high or even moderateaffinity. In addition, or alternatively, certain preferred C5a receptormodulators exhibit an affinity for C5a receptor that is substantiallyhigher than for receptors that do not mediate inflammatory responses(e.g., at least five times higher, at least ten times higher or at least100 times higher). Assays for evaluating binding to receptors that donot mediate inflammatory responses include, for example, those describedin U.S. Pat. No. 6,310,212, which is incorporated herein by referencefor its disclosure of a GABA_(A) receptor binding assays in Examples 14,columns 16-17, in U.S. patent application Ser. No. 10/152,189 which isincorporated herein by reference for its disclosure of an MCH receptorbinding assay in Example 2, pages 104-105, in U.S. Pat. No. 6,362,186,which is incorporated herein by reference for its disclosure of CRF1 andNPY receptor binding assays in Examples 19, columns 45-46, in U.S. Pat.No. 6,355,644, which is incorporated herein by reference for itsdisclosure of a dopamine receptor binding assay at column 10, and inU.S. Pat. No. 6,482,611, which is incorporated herein by reference forits disclosure of VR1 receptor binding assays in Examples 4-5, column14. It will be apparent that the C5a receptor modulators provided hereinmay, but need not, bind to one or more other receptors known to mediateinflammatory responses, such as C3a receptors and/or A₃ receptors.

Certain preferred compounds are C5a receptor antagonists that do notpossess significant (e.g., greater than 5%) agonist activity in any ofthe C5a receptor-mediated functional assays discussed herein.Specifically, this undesired agonist activity can be evaluated, forexample, in the GTP binding assay of Example 52, by measuring smallmolecule mediated GTP binding in the absence of the natural agonist,C5a. Similarly, in a calcium immobilization assay (e.g., that of Example53) a small molecule compound can be directly assayed for the ability ofthe compound to stimulate calcium levels in the absence of the naturalagonist C5a. The preferred extent of C5a agonist activity exhibited bycompounds provided herein is less than 10%, 5% or 2% of the responseelicited by the natural agonist, C5a.

Additionally preferred C5a receptor modulators do not inhibit or inducemicrosomal cytochrome P450 enzyme activities, such as CYP1A2 activity,CYP2A6 activity, CYP2C9 activity, CYP2C19 activity, CYP2D6 activity,CYP2E1 activity or CYP3A4 activity. Preferred C5a receptor modulatorsalso do not exhibit cytotoxicity in vitro or in vivo, are notclastogenic (e.g., as determined using a mouse erythrocyte precursorcell micronucleus assay, an Ames micronucleus assay, a spiralmicronucleus assay or the like) and do not induce sister chromatidexchange (e.g., in Chinese hamster ovary cells). Also preferred are C5areceptor modulators that inhibit the occurrence of C5a-induced oxidativeburst (OB) in inflammatory cells (e.g., neutrophil) as can beconveniently determined using an in vitro neutrophil OB assay.

For detection purposes, compounds provided herein may beisotopically-labeled or radiolabeled. Accordingly, compounds recited inFormula I (or any other formula specifically recited herein) may haveone or more atoms replaced by an atom of the same element having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be present incompounds provided herein include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ²H, ³H,¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl. In addition,substitution with heavy isotopes such as deuterium (i.e., ²H) can affordcertain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements and, hence, may be preferred in some circumstances.

Methods of Use

C5a modulators provided herein may be used as agonists or (preferably)antagonists of C5a receptors in a variety of contexts, both in vitro andin vivo. Within certain aspects, C5a antagonists may be used to inhibitthe binding of C5a receptor ligand (e.g., C5a) to C5a receptor in vitroor in vivo. In general, such methods comprise the step of contacting aC5a receptor with a sufficient amount of one or more substitutedcompound of Formula I as provided herein, in the presence of C5areceptor ligand in aqueous solution and under conditions otherwisesuitable for binding of the ligand to C5a receptor. The C5a receptor maybe present in suspension (e.g., in an isolated membrane or cellpreparation), or in a cultured or isolated cell. Within certainembodiments, the C5a receptor is expressed by a cell present in apatient, and the aqueous solution is a body fluid. In general, dieamount of C5a receptor modulator contacted with the receptor shouldyield a concentration in the aqueous solution sufficient to inhibit C5abinding to C5a receptor in vitro as measured, for example, using aradioligand binding assay as described in Example 51, a calciummobilization assay as described in Example 53, or a chemotaxis assay asdescribed in Example 46. Preferably the concentration is sufficient toinhibit chemotaxis of white blood cells in an in vitro chemotaxis assay,so that the levels of chemotaxis observed in a control assay (e.g., oneto which a compound provided herein has not been added) aresignificantly higher (significance here measured as p≦0.05 using aconventional parametric statistical analysis method such as a student'sT-test) than the levels observed in an assay to which a compound asdescribed herein has been added.

Also provided herein are methods for modulating, preferably inhibiting,the signal-transducing activity of a C5a receptor. Such modulation maybe achieved by contacting a C5a receptor (either in vitro or in vivo)with an effective amount of one or more C5a receptor modulators providedherein under conditions suitable for binding of the modulators) to thereceptor. The receptor may be present in solution or suspension, in acultured or isolated cell preparation or within a patient. Modulation ofsignal transducing activity may be assessed by detecting an effect oncalcium ion conductance (also referred to as calcium mobilization orflux) or by detecting an effect on C5a receptor-mediated cellularchemotaxis. In general, an effective amount of C5a modulator(s) is anamount sufficient to yield a concentration (in an aqueous solution thatis in contact with the receptor) that is sufficient to modulate C5areceptor signal transducing activity in vitro within a calciummobilization assay as described in Example 53 or C5a receptor-mediatedcellular chemotaxis within an assay as described in Example 46. C5areceptor modulator(s) provided herein are preferably administered to apatient (e.g., a human) orally or topically, and are present within atleast one body fluid of the animal while modulating C5a receptorsignal-transducing activity.

The present invention further provides methods for treating patientssuffering from conditions responsive to C5a receptor modulation. As usedherein, the term “treatment” encompasses both disease-modifyingtreatment and symptomatic treatment, either of which may be prophylactic(i.e., before the onset of symptoms, in order to prevent, delay orreduce the severity of symptoms) or therapeutic (i.e., after the onsetof symptoms, in order to reduce die severity and/or duration ofsymptoms). A condition is “responsive to C5a receptor modulation” ifmodulation of C5a receptor activity results reduction of inappropriateactivity of a C5a receptor, regardless of the amount of C5a receptorligand present locally and/or in alleviation of the condition or asymptom thereof. Patients may include primates (especially humans),domesticated companion animals (such as dogs, cats, horses) andlivestock (such as cattle, pigs, sheep), with dosages as describedherein.

Conditions that are responsive to C5a receptor modulation include thefollowing:

Autoimmune disorders—e.g., rheumatoid arthritis, systemic lupuserythematosus and associated glomerulonephritis), psoriasis, Crohn'sdisease, vasculitis, irritable bowel syndrome, dermatomyositis, multiplesclerosis, bronchial asthma, pemphigus, pemphigoid, scleroderma,myasthenia gravis, autoimmune hemolytic and thrombocytopenic states,Goodpasture's syndrome (and associated glomerulonephritis and pulmonaryhemorrhage), immunovasculitis, tissue graft rejection, and hyperacuterejection of transplanted organs.

Inflammatory disorders and related conditions—e.g., neutropenia, sepsis,septic shock, Alzheimer's disease, stroke, inflammation associated withsevere burns, lung injury, and ischemia-reperfusion injury,osteoarthritis, as well as acute (adult) respiratory distress syndrome(ARDS), systemic inflammatory response syndrome (SIRS), and multipleorgan dysfunction syndrome (MODS). Also included are pathologicsequellae associated with insulin-dependent diabetes mellitus (includingdiabetic retinopathy), lupus nephropathy, Heyman nephritis, membranousnephritis and other forms of glomerulonephritis, contact sensitivityresponses, and inflammation resulting from contact of blood withartificial surfaces that can cause complement activation, as occurs, forexample, during extracorporeal circulation of blood (e.g., duringhemodialysis or via a heart-lung machine, for example, in associationwith vascular surgery such as coronary artery bypass grafting or heartvalve replacement) such as extracorporeal post-dialysis syndrome, or inassociation with contact with other artificial vessel or containersurfaces (e.g., ventricular assist devices, artificial heart machines,transfusion tubing, blood storage bags, plasmapheresis,plateletpheresis, and the like).

Cardiovascular and Cerebrovascular Disorders—e.g., myocardialinfarction, coronary thrombosis, vascular occlusion, post-surgicalvascular reocclusion, atherosclerosis, traumatic central nervous systeminjury, and ischemic heart disease.

In a further aspect, C5a receptor modulators may be used to perfuse adonor organ prior to transplantation of the organ into a recipientpatient. Such perfusion is preferably carried out using a solution(e.g., pharmaceutical composition) comprising a concentration of themodulator that is sufficient to inhibit C5a receptor-mediated effects invitro and/or in vivo. Such perfusion preferably reduces the severity orfrequency of one or more of the inflammatory sequalae following organtransplantation when compared to that occurring in control (including,without restriction, historical control) transplant recipients who havereceived transplants of donor organs that have not been so perfused.

Treatment methods provided herein include in general administration to apatient an effective amount of one or more compounds of the invention.Suitable patients include those patients suffering from or susceptibleto (i.e., prophylactic treatment) a disorder or disease identifiedherein. Typical patients for treatment in accordance with the inventioninclude mammals, particularly primates, especially humans. Othersuitable patients include domesticated companion animals such as a dog,cat, horse, and the like, or a livestock animal such as cattle, pig,sheep and the like.

In general, treatment methods provided herein comprise administering toa patient an effective amount of a compound one or more compoundsprovided herein. The effective amount may be an amount sufficient tomodulate C5a receptor activity and/or an amount sufficient to reduce oralleviate the symptoms presented by the patient. Preferably, the amountadministered is sufficient to yield a plasma concentration of theCompound (or its active metabolite, if a pro-drug) high enough todetectably inhibit white blood cell (e.g., neutrophil) chemotaxis invitro. Treatment regimens may vary depending on the compound used andthe particular condition to be treated; for treatment of most disorders,a frequency of administration of 4 times daily or less is preferred. Ingeneral, a dosage regimen of 2 times daily is more preferred, with oncea day dosing particularly preferred. It will be understood, however,that the specific dose level and treatment regimen for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, rate ofexcretion, drug combination (i.e., other drugs being administered to thepatient) and the severity of the particular disease undergoing therapy,as well as the judgment of the prescribing medical practitioner. Ingeneral, the use of the minimum dose sufficient to provide effectivetherapy is preferred. Patients may generally be monitored fortherapeutic effectiveness using medical or veterinary criteria suitablefor the condition being treated or prevented.

As noted above, compounds and compositions provided herein are useful asinhibitors of C5a receptor-mediated chemotaxis (e.g., they may be usedas standards in assays of such chemotaxis). Accordingly, methods areprovided herein for inhibiting C5a receptor-mediated cellularchemotaxis, preferably leukocyte (e.g., neutrophil) chemotaxis. Suchmethods comprise contacting white blood cells (particularly primatewhite blood cells, especially human white blood cells) with one or morecompounds provided herein. Preferably the concentration is sufficient toinhibit chemotaxis of white blood cells in an in vitro chemotaxis assay,so that the levels of chemotaxis observed in a control assay aresignificantly higher, as described above, than the levels observed in anassay to which a compound as described herein has been added.

Within separate aspects, the present invention provides a variety ofnon-pharmaceutical in vitro and in vivo uses for the compounds providedherein. For example, such compounds may be labeled and used as probesfor the detection and localization of C5a receptor (in samples such ascell preparations or tissue sections preparations or fractions thereof).Compounds may also be used as positive controls in assays for C5areceptor activity, as standards for determining the ability of acandidate agent to bind to C5a receptor, or as radiotracers for positronemission tomography (PET) imaging or for single photon emissioncomputerized tomography (SPECT). Such methods can be used tocharacterize C5a receptors in living subjects. For example, a C5areceptor modulator may be labeled using any of a variety of well knowntechniques (e.g., radiolabeled with a radionuclide such as tritium, asdescribed herein), and incubated with a sample for a suitable incubationtime (e.g., determined by first assaying a time course of binding).Following incubation, unbound compound is removed (e.g., by washing),and bound compound detected using any method suitable for the labelemployed (e.g., autoradiography or scintillation counting forradiolabeled compounds; spectroscopic methods may be used to detectluminescent groups and fluorescent groups). As a control, a matchedsample containing labeled compound and a greater (e.g., 10-fold greater)amount of unlabeled compound may be processed in the same manner. Agreater amount of detectable label remaining in the test sample than inthe control indicates the presence of C5a receptor in the sample.Detection assays, including receptor autoradiography (receptor mapping)of C5a receptor in cultured cells or tissue samples may be performed asdescribed by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols inPharmacology (1998) John Wiley & Sons, New York.

Modulators provided herein may also be used within a variety of wellknown cell separation methods. For example, modulators may be linked tothe interior surface of a tissue culture plate or other support, for useas affinity ligands for immobilizing and thereby isolating, C5areceptors (e.g., isolating receptor-expressing cells) in vitro. Withinone preferred embodiment, a modulator linked to a fluorescent marker,such as fluorescein, is contacted with the cells, which are thenanalyzed (or isolated) by fluorescence activated cell sorting (FACS).

Pharmaceutical Preparations

The present invention also provides pharmaceutical compositionscomprising one or more C5a receptor modulators provided herein, togetherwith at least one physiologically acceptable carrier or excipient.Pharmaceutical compositions may comprise, for example, one or more ofwater, buffers (e.g., neutral buffered saline or phosphate bufferedsaline), ethanol, mineral oil, vegetable oil, dimethylsulfoxide,carbohydrates (e.g., glucose, mannose, sucrose or dextrans), mannitol,proteins, adjuvants, polypeptides or amino acids such as glycine,antioxidants, chelating agents such as EDTA or glutathione and/orpreservatives. As noted above, other active ingredients may (but neednot) be included in the pharmaceutical compositions provided herein.

A carrier is a substance that may be associated with an active compoundprior to administration to a patient, often for the purpose ofcontrolling stability or bioavailability of the compound. Carriers foruse within such formulations are generally biocompatible, and may alsobe biodegradable. Carriers include, for example, monovalent ormultivalent molecules such as serum albumin (e.g., human or bovine), eggalbumin, peptides, polylysine and polysaccharides such as aminodextranand polyamidoamines. Carriers also include solid support materials suchas beads and microparticles comprising, for example, polylactatepolyglycolate, poly(lactide-co-glycolide), polyacrylate, latex, starch,cellulose or dextran. A carrier may bear the compounds in a variety ofways, including covalent bonding (either directly or via a linkergroup), noncovalent interaction or admixture.

Pharmaceutical compositions may be formulated for any appropriate mannerof administration, including for example, topical, oral, nasal, rectalor parenteral administration. In certain embodiments, compositions in aform suitable for oral use are preferred. Such forms include, forexample, pills, tablets, troches, lozenges, aqueous or oily suspensions,dispersible powders or granules, emulsion, hard or soft capsules, orsyrups or elixirs. Within yet other embodiments, compositions providedherein may be formulated as a lyophilizate. The term parenteral as usedherein includes subcutaneous, intradermal, intravascular (e.g.,intravenous), intramuscular, spinal, intracranial, intrathecal andintraperitoneal injection, as well as any similar injection or infusiontechnique.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and may contain one or more agents sweetening agents,flavoring agents, coloring agent, and preserving agents in order toprovide appealing and palatable preparations. Tablets contain the activeingredient in admixture with physiologically acceptable excipients thatare suitable for the manufacture of tablets. Such excipients include,for example, inert diluents (e.g., calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate), granulating anddisintegrating agents (e.g., corn starch or alginic acid), bindingagents (e.g., starch, gelatin or acacia) and lubricating agents (e.g.,magnesium stearate, stearic acid or talc). The tablets may be uncoatedor they may be coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as lard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent(e.g., calcium carbonate, calcium phosphate or kaolin), or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium (e.g., peanut oil, liquid paraffin or olive oil).

Aqueous suspensions contain the active material(s) in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients include suspending agents (e.g., sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and grum acacia);and dispersing or wetting agents (e.g., naturally-occurring phosphatidessuch as lecithin, condensation products of an alkylene oxide with fattyacids such as polyoxyethylene stearate, condensation products ofethylene oxide with long chain aliphatic alcohols such asheptadecaethyleneoxycetanol, condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides such as polyethylene sorbitan monooleate). Aqueoussuspensions may also comprise one or more preservatives, for exampleethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one ormore flavoring agents, and one or more sweetening agents, such assucrose or saccharin. Syrups and elixirs may be formulated withsweetening agents, such as glycerol, propylene glycol, sorbitol, orsucrose. Such formulations may also comprise one or more demulcents,preservatives, flavoring agents, and/or coloring agents.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil (e.g., arachis oil, olive oil, sesame oil, or coconutoil) or in a mineral oil such as liquid paraffin. The oily suspensionsmay contain a thickening agent such as beeswax, hard paraffin, or cetylalcohol. Sweetening agents, such as those set forth above, and/orflavoring agents may be added to provide palatable oral preparations.Such suspensions may be preserved by the addition of an anti-oxidantsuch, as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions may also be in the form of oil-in-wateremulsions. The oily phase may be a vegetable oil (e.g., olive oil orarachis oil), a mineral oil (e.g., liquid paraffin), or a mixturethereof. Suitable emulsifying agents include naturally-occurring gums(e.g., gum acacia or gum tragacanth), naturally-occurring phosphatides(e.g., soy bean, lecithin, and esters or partial esters derived fromfatty acids and hexitol), anhydrides (e.g., sorbitan monoleate), andcondensation products of partial esters derived from fatty acids andhexitol with ethylene oxide (e.g., polyoxyethylene sorbitan monoleate).An emulsion may also comprise one or more sweetening and/or flavoringagents.

The pharmaceutical composition may be prepared as a sterile injectableaqueous or oleaginous suspension in which the modulator, depending onthe vehicle and concentration used, is either suspended or dissolved inthe vehicle. Such a composition may be formulated according to the knownaft using suitable dispersing, wetting agents and/or suspending agentssuch as those mentioned above. Among the acceptable vehicles andsolvents that may be employed are water, 1,3-butanediol, Ringer'ssolution and isotonic sodium chloride solution. In addition, sterile,fixed oils may be employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid may be usedin the preparation of injectable compositions, and adjuvants such aslocal anesthetics, preservatives and/or buffering agents can bedissolved in the vehicle.

C5a receptor modulators may also be administered in the form ofsuppositories (e.g., for rectal administration). Such compositions canbe prepared by mixing the drug with a suitable non-irritating excipientthat is solid at ordinary temperatures but liquid at the rectaltemperature and will therefore melt in the rectum to release the drug.Such materials are cocoa butter and polyethylene glycols.

Pharmaceutical compositions may be formulated as sustained releaseformulations (i.e., a formulation such as a capsule that effects a slowrelease of modulator following administration). Such formulations maygenerally be prepared using well known technology and administered by,for example, oral, rectal, or subcutaneous implantation, or byimplantation at the desired target site. Carriers for use within suchformulations are biocompatible, and may also be biodegradable;preferably the formulation provides a relatively constant level ofmodulator release. The amount of modulator contained within a sustainedrelease formulation depends upon, for example, the site of implantation,the rate and expected duration of release and the nature of thecondition to be treated or prevented.

In addition to or together with the above modes of administration, amodulator may be conveniently added to food or drinking, water (e.g.,for administration to non-human animals including companion animals(such as dogs and cats) and livestock). Animal feed and drinking watercompositions may be formulated so that the animal takes in anappropriate quantity of the composition along with its diet. It may alsobe convenient to present the composition as a premix for addition tofeed or drinking water.

C5a receptor modulators provided herein are generally administered in anamount that achieves a concentration in a body fluid (e.g., blood,plasma, serum, CSF, synovial fluid, lymph, cellular interstitial fluid,tears or urine) that is sufficient to detectably inhibit the binding ofC5a to C5a receptor when assayed in vitro. A dose is considered to beeffective if it results in a discernible patient benefit as describedherein. Preferred systemic doses range from about 0.1 mg to about 140 mgper kilogram of body weight per day (about 0.5 mg to about 7 g perpatient per day), with oral doses generally being about 5-20 fold higherthan intravenous doses. The amount of active ingredient that may becombined with the carrier materials to produce a single dosage form willvary depending upon the host treated and the particular mode ofadministration. Dosage unit forms will generally contain between fromabout 1 mg to about 500 mg of an active ingredient.

Pharmaceutical compositions may be packaged for treating conditionsresponsive to C5a receptor modulation (e.g., rheumatoid arthritis,psoriasis, cardiovascular disease, reperfusion injury, bronchial asthma,Alzheimer's disease, stroke, myocardial infarction, atherosclerosis,ischemic heart disease or ischemia-reperfusion injury). Packagedpharmaceutical compositions may include a container holding a effectiveamount of at least one C5a receptor modulator as described herein andinstructions (e.g., labeling) indicating that the contained compositionis to be used for treating a condition responsive to C5a receptormodulation in the patient

Preparation of Compounds

Representative methods for preparing the compounds of the invention areshown in the following Schemes. A number of abbreviations are used inthe schemes and accompanying examples and are listed here.

ABBREVIATIONS USED DMF dimethylformamide DMA dimethylacetamide DMEethylene glycol dimethyl ether THF tetrahydrofuran DMSO dimethylsulfoxide DCM dichloromethane DCE 1,2-dichloroethane MeOH methanol EtOHethanol Et₂O diethyl ether Hex hexane HOAc acetic acid AcOH acetic acidNaOAc sodium acetate AcONa sodium acetate TFA trifluoroacetic acid pTsOHp-toluenesulfonic acid HCl hydrochloric acid H₃O⁺ aqueous acid HCHOformaldehyde TEA triethylamine MsCl methanesulfonyl chloride MeLi methyllithium n-BuLi n-butyllithium SAMP (S)-(−)-1-amino-2-(methoxymethyl)pyrrolidine RAMP (R)-(+)-1-amino-2-(methoxymethyl)pyrrolidine EtOAc ethyl acetate NaOEt sodium ethoxideNaOH sodium hydroxide KOH potassium hydroxide NH₄OH ammonium hydroxideNH₃—H₂O ammonium hydroxide Na₂SO₄ sodium sulfate MgSO₄ magnesium sulfateK₂CO₃ potassium carbonate Cs₂CO₃ cesium carbonate NaH sodium hydride MeIiodomethane BuBr n-butyl bromide n-BuI n-butyl iodide NaCl sodiumchloride NaI sodium iodide CDI 1,1′-carbonyldiimidazole SOCl₂ thionylchloride POCl₃ phosphorous oxychloride Me₂NH dimethyl amine RB(OH)₂alkyl or aryl boronic acid Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium (0) NaBH₄ sodium borohydride BH₃ borane NaBH(OAc)₃ sodiumtriacetoxyborohydride Br₂ bromine NBS N-bromosuccinimde NCSN-chlorosuccinimde CuBr₂ copper (II) bromide DAST (diethylamino)sulfurtrifluoride [O] oxidation AgNO₃ silver nitrate DDQ2,3-dichloro-5,6-dicyano-1,4-benzophenone MnO₂ manganese (II) dioxideSiO₂ silica LC-MS liquid chromatography/mass spectrometry HPLC highpressure liquid chromatography TLC thin layer chromatography ¹H NMRproton nuclear magnetic resonance MHz megahertz Hz hertz δ chemicalshift CDCl₃ deuterated chloroform MS mass spectrometry m/z mass/chargeratio (M + 1) mass + 1 [α]_(D) specific rotation c concentration eq.equivalentsWithin Schemes 1-10 the variables e.g. Ar₁, Ar₂, R₁, R₂, R₃ and R₄, aredefined as above for Formula I, unless otherwise specified.

As shown in Scheme 1, an appropriately substituted arylnitrile 10 isconverted to the imidate 11 via treatment with hydrogen chloride gas inmethanol followed by subsequent treatment with base to release the freebase. Amidine 12 is prepared from 11 by treatment with a primary amine.2-Arylimidazole-4-carboxaldehyde 13 is prepared from 12 by one ofseveral methods described in the chemical literature, for instance, bytreatment with) 2-bromo-3-isopropoxyacrolein in the presence of base.See, for example, J. Org. Chem., 62: 8449 (Shilcrat et al., 1997).

Aldehyde 13 can then be transformed into hydroxymethylimidazole bytreatment with the appropriate organometallic. The hydroxy group of 14is converted to either a halogen or sulfonate ester leaving group.Treatment of this intermediate with an appropriate secondary amine inthe presence of base provides 2-aryl-4-aminomethylimidazole 15.Alternatively, the aminoalkyl functionality of 15 may be elaborated bysequential amination-acylation-reduction steps. In situations where R₁is a halogen, it may be prepared from 15 (R₁═H) by treatment with themolecular halogen, a halosuccinimide or the like.

As shown in Scheme 2, an appropriately substituted 2-aryl-4-substitutedimidazole 20 can be N-alkylated by treatment with base such as sodiumhydride, and an alkyl halide, or alkylsulfonate ester to provide thetrisubstituted imidazole 21. Hydroxymethylation of 21 under theconditions of the Mannich reaction provides hydroxymethylimidazole 22.In examples where R₃ is alkyl, the hydroxymethyl derivative 24 isprepared from 22 by oxidation to aldehyde 23 and subsequent treatmentwith an appropriate organometallic reagent such as an alkyl lithium orGrignard reagent. Conversion of 22 or 24 to the desired2-aryl-5-aminomethylimidazoles is carried out by conversion of thehydroxymethyl to a halogen or sulfonate ester leaving group followed bytreatment with a secondary amine. Alternatively, the aminoalkylfunctionality of the 2-aryl-5-aminomethylimidazole product may beelaborated by sequential amination-acylation-reduction steps.

The 2-aryl-4-substitutedimidazole 20 may be prepared by methodsdescribed in the chemical literature, for instance, via condensation ofan arylamidine with a halomethyl or hydroxymethyl ketone.

An illustration of the preparation of compounds of theCycloalkylimidazole compounds of the present invention is given inScheme 3. Within Scheme 3 the variables Ar₁, Ar₂, R₂, R₃, and R₄ are asdefined previously. As shown in Scheme 3, an appropriately substitutedarylamidine 30 is condensed with an appropriately substituted2-halo-3-alkoxyenone 31 to provide a 2-aryl-4,5-cycloalkylimidazole 32.The ketone functionality of 32 can be reduced to give the cyclic alcohol33 Compounds of general formula 34 can be prepared from 33 by one ofseveral methods described in the chemical literature, for instance, bytreatment with thionyl chloride or by treatment with an alkyl orarylsulphonyl chloride in the presence of base.

Compounds of formula 34 can then be transformed into compounds ofgeneral Formula 35 by direct treatment with the appropriate secondaryamine. Alternatively, the X functionality of 34 may be transformed intoa tertiary amine in a stepwise manner. In this case, 34 would be treatedwith a primary amine to provide an intermediate secondary amine. This,in turn, could be alkylated to give cycloalkylimidazole compounds of theinvention.

An illustration of the preparation of pyridine compounds of the presentinvention is given in Scheme 4. Those having skill in the art willrecognize that the starting materials may be varied and additional stepsemployed to produce compounds encompassed by the present invention.Within Scheme 4 the variables Ar₁, Ar₂, R, R₁, R₂, R₃, and R₄ aredefined as previously described.

As shown in Scheme 4, an appropriately substituted 4-phenyloxazole 40 iscondensed with an appropriately substituted maleic acid to provide a2-phenylisonicotinic acid 41. The carboxylic acid functionality of 41can be reduced directly to the primary alcohol (43, R₃H) or converted bymethods known to the art to an intermediate aldehyde 42 and subsequentlytreated with the appropriate organometallic (for cases where R₃ isalkyl) to give a secondary alcohol 43. Compounds of general formula 44can be prepared from 43 by one of several methods described in thechemical literature, for instance, by initial treatment with thionylchloride or with an alkyl or arylsulphonyl chloride in the presence ofbase, followed by subsequent condensation with a primary amine.Compounds of formula 44 can then be transformed into compounds offormula 45 by direct treatment with the appropriate alkylating agent or,alternatively, by reductive alkylation. Alternatively, the tertiaryamine functionality of formula 45 may be realized directly fromcompounds of formula 43 by initial treatment with thionyl chloride orwith an alkyl or arylsulphonyl chloride in the presence of base,followed by subsequent condensation with a secondary amine.

An illustration of the preparation of arylpyrazole compounds of thepresent invention is given in Scheme 5. Within Scheme 5 the variablesAr₁, Ar₂, R₁, R₂, R₃, and R₄ are defined as previously described.

As shown in Scheme 5, an appropriately substituted phenylhydrazineadduct 50 is condensed with an appropriately substituted α-ketoester 51,in the presence of a Lewis acid, preferably ZnCl₂, with heating at50-200° C., preferably at 125° C. to provide a 1-phenylpyrazole ester52. The carboxylic acid functionality of 52 can be reduced directly tothe primary alcohol (53, R₃═H) or converted by methods known to the artto an intermediate aldehyde and subsequently treated with theappropriate the appropriate organometallic (for cases where R₃ is alkyl)to give a secondary alcohol 53. Compounds of general formula 54, whereLG represents a leaving group, can be prepared from 53 by one of severalmethods described in the chemical literature, for instance, by initialtreatment with thionyl chloride or with an alkyl or arylsulphonylchloride in the presence of base, followed by subsequent condensationwith a primary amine. Compounds of formula 54 can then be transformedinto compounds of formula 58 by sequential treatment with theappropriate primary amine followed by direct alkylation or reductivealkylation of the intermediate secondary amine. Alternatively, thetertiary amine functionality of formula 58 may be realized directly fromcompounds of formula 53 by initial treatment with thionyl chloride orwith an alkyl or arylsulphonyl chloride in the presence of base,followed by subsequent condensation with a secondary amine.

An alternative route to the preparation of compounds of Formula 58 fromthe 1-phenylpyrazole ester 52 may be realized by hydrolysis of 52 to acarboxylic acid of general structure 56, followed by amide formation toprovide 57 and, finally, reduction of the amide functionality to thetertiary amine of 58 (R₃═H).

The preparation of 6-aryl-pyridazine is shown in Scheme 6. Thebromoketone 61 is prepared by treatment of the corresponding ketone 60with two equivalents CuBr₂ refluxing in CHCl₃ and EtOAc. After workupand without further purification, these bromoketones are reacted withNaH and dimethyl malonate 62 to give the adduct ketodiester 63.Decarboxylation of 63 with NaCl/H₂O in DMSO at 155-160° C. providesketoester 64 cleanly. Condensation of 64 with hydrazine monohydraterefluxing in EtOH furnishes the dihydro-pyridazinone 65. Aromatizationof 65 is accomplished by treatment of it with Br₂ in HOAc at 80° C. Theresulting pyridazinone 66 is then converted into chloropyridazine 8 byheating 66 in POCl₃ at 85° C. for 3 hours. Free radicalhydroxymethylation of 67 by heating with (NH₄)₂S₂O₈ and H₂SO₄ with acatalytic amount of AgNO₃ in methanol and water provides the desired5-hydroxymethyl pyridazine 68 in low to moderate yield. Subsequentlytreatment of 68 with SOCl₂ gives the chloromethyl pyridazine 69 as ahydrochloric salt. Compound 69 then is converted to secondary amine 70by reacting with various primary amines in presence of excess K₂CO₃ inCH₃CN. Finally, reductive amination of 70 with wide range of aldehydesprovides the desired 6-aryl-pyridazine compound 71. In some cases, 71can be prepared directly from 69 by treatment with a secondary amine andK₂CO₃ in refluxing CH₃CN.

Scheme 7 illustrates a method for preparing pyrimidines of Formula Iwhere R₁ is hydrogen. In step 1, an appropriately substitutedarylalkylketone is reacted with dimethylformamide dimethyl acetal toproduce the corresponding enaminoketone. The enaminoketone intermediateis heated in a sealed tube with formamidine acetate to obtain thecorresponding 4,5-disubstituted pyrimidine in step 2. In step 3,addition of methyllithium to the pyrimidine yields the corresponding1,6-dihydropyrimidine which is oxidized in situ with DDQ(2,3-dichloro-5,6-dicyano-1,4-benzoquinone) to yield the4,5,6-trisubstituted pyrimidine which is subsequently brominated to formthe 6-(bromomethyl)pyrimidine. In step 4, reaction with variousappropriately substituted secondary amines provides pyrimidines offormula I. Those skilled in the art will realize that minormodifications to this synthetic route can be used to obtain differentlysubstituted pyrimidines of Formula I. For example, use of alkylamidinesin step 2 can be used to obtain compounds of Formula I where R₁ isalkyl.

Scheme 8 illustrates a route for preparing pyrimidines of Formula Iwhere R₁ is alkoxy. In step 1, an appropriately substituted1,3-ketoester is reacted with thiourea in the presence of base to obtainthe corresponding 2-thioxo-2,3-dihydro-1H-pyrimidin-4-one which ishydrolyzed in step 2 to the corresponding 1H-pyrimidine-2,4-dione. Instep 3, the 1H-pyrimidine-2,4-dione is reacted with phosphorousoxychloride and dimethylformamide to obtain the corresponding2,4-dichloropyrimidine. This material is reacted under Suzuki couplingconditions in step 4 to replace the 4-chloro group with Ar₁. Brominationand subsequent reaction with appropriate secondary amines in steps 5 and6 provides 2-chloropyrimidines of Formula I. Displacement of the2-chloro substituent in step 7 provides 2-alkoxypyrimidines of Formula I(NaOR′ represents an appropriate sodium alkoxide). Those skilled in theart will realize that minor modifications to Scheme 8 can be used toobtain differently substituted pyrimidines of Formula I. For example,displacement of the 2-chloro substituent with amines in step 7 can beused to obtain 2-aminopyrimidines of Formula I.

Scheme 9 illustrates a route for preparing imidazoles of Formula I whereR₁ is aryl or heteroaryl and Ar₁ is a variety of aryl and heterarylgroups. In step 1, an aryl imidazole 82 is alkylated to obtain anisomeric mixture. This mixture is separated by chromatography to providethe desired isomer 83. In step 2, imidazole 83 is lithiated at the2-position and reacted with an electrophilic iodine or bromine source toprovide 2-haloimidazole 84. In step 3, imidazole 84 is converted to thecorresponding hydroxymethyl derivative by heating under pressure withaqueous formaldehyde in the presence of acetic acid and sodium acetateto yield 85. Hydroxymethylimidazole 85 is converted to the chloride andused to alkylate various airlines in step 4 to obtainaminomethylimidazoles 86. Reductive amination of aminomethylimidazole 86in step 5 provides 2-haloimidazole 87. Step 6 illustrates a particularset of conditions for conversion of 2-haloimidazole 87 to imidazoles offormula I. Those skilled in the art will recognize that the routeillustrated in Scheme 8 can be modified by changing the sequence ofsteps or the reactants to produce a wide variety of imidazoles ofFormula I. For example, 2-haloimidazole 87 can be coupled withalternative organometallics (Ar₁M, M=Sn, Mg, Zn) to enhance the varietyof imidazoles of Formula I accessible by this route.

Scheme 10 illustrates a route for preparing imidazoles of Formula Iutilizing trihaloimidazole 90. In steps 1 and 2, 90 is prepared fromdihaloimidazole 88 by alkylation with R₂Y wherein Y is a suitableleaving group such as bromo, iodo or mesylate followed by electrophilicbromination. In step 3, 90 is selective coupled at the 2-position withvarious aryl boronic acids in the presence of palladium catalyst. Instep 4, metal-halogen exchange occurs selectively at the 5-position of91 to yield, after reaction with DMF, aldehyde 92. In steps 5 and 6,aldehyde 92 is reduced to the corresponding alcohol 93, activated as thechloride and displaced with an appropriately substituted amine to yieldimidazoles compounds of Formula I, where R₁ is chloro or bromo (94).Optional subsequent steps may be employed to convert X to a variety ofR₁ substituents according to the Formula I. As illustrated in Schemes1-9 and the accompanying examples, a variety of straight-forwardmodifications to Scheme 10 can be employed to access a wide variety ofcompounds of Formula I.

Scheme 11 illustrates a route for preparing imidazoles of Formula Iwherein R₃ is incorporated in a stereospecific manner in a similarmanner to a published procedure (Enders, D.; Thiebes, C. J. Synthesis2000, 510-512).

EXAMPLES

The general methods given in Schemes 1 to 11 above for the preparationof compounds of the present invention are further illustrated by thefollowing examples. Specifically, the methods given in Schemes 1 and 2for the preparation of aryl imidazoles are illustrated by Examples 1-9,shown below. An example of the method shown in Scheme 3 for thepreparation of cycloalkylimidazoles is given in example 10, an exampleof the method shown in Scheme 4 for the preparation of arylpyridines isgiven in example 11, and an example of the method shown in Scheme 5 forthe preparation of arylpyrazoles is further illustrated in examples 12and 14. Example 13 provides a method for the synthesis of arylsubstituted triazoles. Methods for the synthesis of aryl substitutedpyridizines are given in examples 15-18. Methods for the synthesis ofcompounds in which y is greater than 1 are given in examples 19 and 22.Examples 20-21 provide methods for the synthesis of 4-aryl-pyrimidines.Examples 22 and 24-26 provide supporting chemistry for the synthesis ofcompounds of Formula I bearing some particular functionalized Ar₂ orR₄substituents. Example 23 further illustrates the route outlined inScheme 9. Examples 27 and 28 further illustrates the chiral synthesis ofR₃=alkyl compounds described in Scheme 11. Examples 29-40 are providedto illustrate the synthesis of a variety of intermediates and compoundswherein R₃ is substituted alkyl. Example 41 provides for the synthesisof intermediates used in the synthesis of certain compounds preparedaccording to Scheme 10. Unless otherwise specified all startingmaterials and reagents are of standard commercial grade, and are usedwithout further purification, or are readily prepared from suchmaterials by routine methods. Those skilled in the art of organicsynthesis will recognize that starting materials and reaction conditionsmay be varied to achieve the desired end product.

Example 1 Preparation of an Arylimidazole Compound:1-(1-Butyl)-2-phenyl-5-(N,N-di[3,4-methlenedioxyphenylmethyl])aminomethylimidazole (Compound 106)

N-(n-butyl)-benzamidine (101). 7 ml of triethylamine is added to asolution of methyl benzimidate hydrochloride (12 g, 0.07 mole) indimethylformamide (DMF, 20 mL) at 0° C. After 2 h the reaction isfiltered to remove triethylamine hydrochloride. 3.68 g of 1-butylamineis added to the filtrate and the mixture is heated to 60° C. for 6hours. After cooling the mixture is partitioned between ethyl acetateand water. The organic layer is washed with brine, dried over sodiumsulfate, and concentrated to provide the amidine as a yellow oil. ¹H NMR(400 MHz, CDCl₃) δ 7.55 (m, 2H), 7.4 (m, 3H), 3.37 (bm, 2H), 1.62 (m,2H), 1.42 (m, 2H), 0.95 (t, J=7 Hz, 3H).

1-(1-Butyl)-2-phenylimidazole-5-carboxaldehyde (102). Potassiumcarbonate (15.5 g) and water (19 mL) are added to a solution of 101(13.28 g) and 2-bromo-3-isopropoxyacrolein (22g) in chloroform (150 mL).The mixture is stirred at room temperature overnight. The aqueous layeris discarded and the organic layer is washed with water (3×100 ml),dried (Na₂SO₄) and concentrated. The residue is purified via flashchromatography (5% MeOH/CHCl₃) to provide the desired imidazolecarboxaldehyde as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 9.75 (s,1H), 7.90 (s, 1H), 7.55 (m, 2H), 7.45 (m, 3H), 4.38 (t, J=8 Hz, 2H),1.75 (m, 2H), 1.22 (m, 2H), 0.91 (t, J=7 Hz, 3H).

1-(1-Butyl)-2-phenyl-5-hydroxymethylimidazole (103). Aldehyde 102 isdissolved in methanol (150 mL). Sodium borohydride (3g) is added inportions. After the addition is complete, the reaction is diluted withwater and concentrated. The residue is dissolved in ethyl acetate,washed with brine, dried (Na₂SO₄) and concentrated. The product ispurified by flash chromatography on silica gel (5% MeOH/CHCl₃) to give103 as a cream colored solid. ¹H^(NMR) (400 MHz, CDCl₃) δ 0.79 (3H, t,J=7.4 Hz), 1.18 (2H, m, J=7.4 Hz), 1.60 (2H, m, J=7.6 Hz), 4.03 (2H, dd,J=7.6 Hz), 4.56 (2H, s), 6.84 (1H, s), 7.39-7.50 (3H, m), 7.50-7.53 (2H,m).

1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl])aminomethylimidazole (104). Hydroxymethylimidazole 103 (0.82) is dissolved inchloroform (10 mL) and treated with thionyl chloride (1 mL). Thesolution is heated to 50° C. for 30 min, cooled and evaporated. Theresidue is washed with benzene and evaporated to give the intermediatechloromethyl hydrochloride as a white powder which is taken up inacetonitrile (30 ml). This is added dropwise to a solution ofpiperonylamine (5 mL) in acetonitrile (10 mL). The reaction is allowedto stand overnight and then evaporated. The residue is taken up in ethylacetate and washed with water. The organic layer is dried (Na₂SO₄) andconcentrated. Purification on silica gel (10% MeOH/CHCl₃) provides theproduct as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 0.79 (3H, t,J=7.4 Hz), 1.18 (2H, m, J=7.4 Hz), 1.56 (2H, m, J=7.4 Hz), 3.75 (4H, s),4.04 (2H, dd, J=8 Hz), 5.92 (2H, s), 6.76 (2H, m), 6.84 (1H,s), 6.97(1H, s), 7.38-7.44 (3H, m), 7.53-7.56 (2H, m).

1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-(3,4-methylenedioxyphenylcarboxy]) aminomethylimidazole (105).Compound 104 (160 ma, 0.44 mmol) is dissolved in chloroform (5 ml,pentene stabilized) and treated sequentially with piperonyl chloride(100 mg) and triethylamine (1 mL). The mixture is stirred at roomtemperature overnight. The solution is concentrated and the residuetaken up in ethyl acetate. The organic is washed with water, dried(Na₂SO₄) and concentrated Purification by preparative thin layerchromatography (5% MeOH/CHCl₃) provides compound 105 as a pale yellowoil. ¹H^(NMR) (400 MHz, CDCl₃): δ 0.75 (3H, br), 1.16 (2H, br), 1.49(2H, br), 4.01 (2H, hr), 4.54 (2H, br), 4.68 (2H, br), 5.97 (2H, s),5.99 (2H, s), 6.66 (2H, d, J=7.2 Hz), 6.80 (2H, t, J=8 Hz), 6.98-7.02(2H, m), 7.40-7.47 (3H, m), 7.56 (2H, d, J=6.8 Hz).

1-(1-Butyl)-2-phenyl-5-(N,N-di[3,4-methylenedioxyphenylmethyl])-aminomethylimidazole(106). Amide 105 (215 mg) in tetrahydrofuran (THF, 3 mL) is addeddropwise to a solution of alane (1 M in THF, 2 mL) and the resultingsolution is stirred for 2.5 h at room temperature. A solution of sodiumhydroxide (15% NaOH, 1 mL) is added and the mixture is extracted withchloroform. The organic extracts are dried (Na₂SO₄) and concentrated.Purification by preparative thin layer chromatography (10% MeOH/CHCl₃)provided compound 106 as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ0.70 (3H, t, J=7.6 Hz), 0.98 (2H, m, J=7.6 Hz), 1.30 (2H, m), 3.44 (4H,s), 3.52 (2H, s), 3.98 (2H, dd, J=8 Hz), 5.92 (4H, s), 6.74 (4H, s),6.69 (2H, s), 7.02 (1H, s), 7.36-7.42 (3H, m), 7.54 (2H, dd, J=1.4, 6.6Hz). The hydrochloride salt (m.p. 187-190° C.) is prepared inisopropanol.

Example 2 Preparation of1-(1-Butyl)-2-phenyl-5-(1-[N-{3,4-methylenedioxyphenylmethyl}-N-phenylmethyl]amino)ethylimidazole(Compound 108)

1-Butyl-2-phenyl-5-(1-hydroxyethyl)imidazole (107). A solution ofaldehyde 102 (230 mg) in diethyl ether (30 mL) is placed in a separatoryfunnel and treated with a solution of methyl lithium (1.4 M in THF, 1.5mL). After 10 min, the solution is washed with ammonium chloridesolution (1 M, 20 mL), dried (Na₂SO₄) and concentrated. The resultingdark oil is purified by preparative TLC (10% MeOH/CHCl₃) to providecompound 107 as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.56 (d, J=2Hz, 2H), 7.4 (m, 3H), 7.01 (s, 1H), 4.86 (q, J=7 Hz, 1H), 4.18 (m, 1H),4.0 (m, 1H), 1.63 (d, J=6.6 Hz, 3H), 1.63 (m, 2H), 1.23 (m, 2H), 0.81(t, J=7 Hz, 3H).

1-Butyl-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]-N-phenylmethyl)aminoethylimidazole(108). A solution of compound 107 (80 mg) in chloroform (10 mL) istreated with thionyl chloride (1 mL) and heated to 50° C. for 30minutes. The solution is then concentrated, diluted with chloroform andreconcentrated to provide the intermediate chloromethyl hydrochloride asan oil. This material is taken up in chloroform (5 mL) and treatedsequentially with N-benzylpiperonylamine (80 mg) and triethylamine.After stirring overnight, the reaction is washed with saturatedpotassium carbonate solution, dried (Na₂SO₄) and concentrated.Purification by preparative thin layer chromatography (10% MeOH/CHCl₃)provides compound 108 as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ7.46-7.43 (m, 1H), 7.2-7.3 (m, 9H), 6.74-6.86 (m, 4H), 5.94 (s, 2H),4.82 (q, J=6.8 Hz, 1H), 4.33 (m, 2H), 3.78 (s, 2H), 3.53 (s, 2H), 1.83(d, J=6.8 Hz, 3H), 1.62-1.68 (m, 2H), 1.21 (q, J=7.8 Hz, 2H), 0.82 (t,J=7.8 Hz, 3H).

Example 3 Preparation of1-Butyl-2-phenyl-4-bromo-5-(N-phenylmethyl-N-[1-butyl])amino-methylimidazole(compound 110)

1-Butyl-2-phenyl-5-(N-benzyl-N-butyl)aminomethylimidazole (109). Asolution of compound 102 (115 mg) and N-butylbenzylamine (85 mg) intoluene (10 mL) is allowed to stand overnight. Treatment of the reactionwith sodium borohydride (100 mg) and ethanol (2 mL) followed by aqueousworkup and purification on silica gel (10% MeOH/CHCl₃) provides compound109 as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.2-7.5 (m, 10H), 6.98(s, 1H), 4.0 (t, J=8 Hz, 2H), 3.55 (s, 2H), 3.52 (s, 2H), 2.42 (t. J=8Hz, 2H), 1.2-1.55 (m, 6H), 1.05 (m, 2H), 0.84 (t, J=7 Hz, 3H), 0.72 (t,J=7 Hz, 3H).

1-Butyl-2-phenyl-4-bromo-5-(N-phenylmethyl-N-[1-butyl])aminomethylimidazole (110). N-bromosuccinimide (16 mg) is added to a solution of109 (30 mg) in acetonitrile (4 mL). The resulting mixture is heated to60° C. and the progress of the reaction followed by TLC. The cooledreaction mixture is diluted with ethyl acetate and washed twice withwater. Purification by preparative thin layer chromatography (10%MeOH/CHCl₃) provides compound 110 as a colorless oil. ¹H NMR (400 MHz,CDCl₃) δ 7.2-7.5 (m, 10H), 3.98 (t, J=8 Hz, 2H), 3.55 (s, 2H), 3.53 (s,2H), 2.46 (t, J=7 Hz, 2H), 1.52 (m, 2H), 1.3 (m, 4H), 0.98 (q, J=7 Hz,2H), 0.84 (t, J=7 Hz, 3H), 0.70 (t, J=7 Hz, 3H).

Example 4 Preparation of1-(1-Butyl)-2-phenyl-4-methyl-5-(N-[3,4-methylenedioxyphenyl-methyl]-N-phenylmethyl)aminomethylimidazole(Compound 114)

1-Butyl-2-phenyl-4-methylimidazole (112). Sodium hydride (4.4 g, 60% inmineral oil) is added to a solution of 4-methyl-2-phenylimidazole (111,15.8 g) in dimethylformamide (100 mL) in small portions. After theaddition is complete, the mixture is stirred for an additional 20minutes and treated with l-iodobutane (18.8 g). The reaction is fittedwith a reflux condenser and heated at 100° C. for 12 hours. The cooledreaction mixture is partitioned between water (300 mL) and diethyl ether(300 ml). The organic layer is washed with water (3×200 mL), dried(Na₂SO₄) and concentrated to provide N-butylimidazoles. Analysis by ¹HNMR and GC-MS revealed mixture of 1-butyl-2-phenyl-4-methylimidazole(112) and 1-butyl-2-phenyl-5-methylimidazole in a ratio of 11.5/1. Themixture is carried to the next step without purification.

1-Butyl-2-phenyl-4-methyl-5-hydroxymethylimidazole (113). A solution of112 (1g) in acetic acid (10 mL) and 40% aqueous formaldehyde (2 mL) isrefluxed for 14 hours. The reaction is then concentrated and dried byrepeated reconcentration with toluene. The residue is purified by columnchromatography (10% MeOH/CHCl₃). The fractions are assayed by GC andthose fractions uncontaminated by the isomeric hydroxymethylimidazolecombined. Concentration of the combined fractions provides compound 113(320 mg) as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.4-7.6 (m,6H), 4.61 (s, 2H, CH₂OH), 4.02 (t, J=7 Hz, 2H, NCH₂), 2.22 (s, 3H, Me),1.63 (m, 2H, 1.25 (m, 2H), 0.81 (t, J=7 Hz, 3H).

1-Butyl-2-phenyl-4-methyl-5-(N-benzyl-N-butyl)aminomethylimidazole(114). Compound 114 (23 mg) is prepared from 113 (50 mg) in a methodsimilar to that used to obtain compound 108. ¹H NMR (400 MHz, CDCl₃) δ7.5-7.55 (m,2H), 7.38-7.42 (m, 3H), 7.23-7.30 (m, 5H), 3.95 (t, J=7.5Hz, 2H), 3.55 (s, 2H), 3.53 (s, 2H), 2.40 (t, J=7 Hz, 2H), 2.22 (s, 3H),1.25-1.40 (m, 6H), 1.05 (m, 2H), 0.82 (t, J=7 Hz, 3H), 0.70 (t, J=7 Hz,3H); MS (LCMS) m/e 390 (M⁺+1)

Example 5 Preparation of1-Butyl-2,4-diphenyl-5-(N-butyl-N-benzyl)aminomethylimidazole (118)

1-Butyl-2,4-diphenylimidazole (116). 1-Iodobutane-(1.5 g) is added to asolution of 2,4-diphenylimidazole 115 (1.76 g, 8 mmol) and cesiumcarbonate (2.6 g, 8 mmol) in 10 ml of DM. The resulting mixture isheated at 80° C. for 16 hours. After cooling, the reaction ispartitioned between water and ether. The ether layer is dried (Na₂SO₄)and concentrated to provide the desired N-alkyl imidazole as an oil(2.2g). ¹H NMR (CDCl₃) 7.82 (d, J=5 Hz, 2H), 7.63 (d, J=4 Hz, 2H),7.2-7.5 (m, 7H), 4.0 (t, J=7 Hz, 2H), 1.77 (m, 2H0, 1.3 (m, 2H), 0.88(t, J=7 Hz, 3H).

1-Butyl-2,4-diphenyl-5-hydroxymethylimidazole (117).1-Butyl-2,4-diphenylimidazole (3 g)is dissolved in 50 ml of acetic acidwith 50 ml of 37% aqueous formalin solution. The mixture is heated atreflux for 48 h, cooled and the solvents evaporated. The residue istriturated with ether and filtered. The filtrate is concentrated andpartitioned between ethyl acetate (100 mL) and 5% aqueous acetic acid(100 mL). The aqueous layer is extracted with ethyl acetate (100 mL).The combined organic extracts are washed with 1N NaOH solution, brine,dried over Na₂SO₄, and concentrated. The crude product is trituratedwith ethyl acetate to give the product as a white solid, ¹H NMR (CDCl₃)7.73 (d, J=5 Hz, 2H), 7.62 (d, J=4 Hz, 2H), 7.3-7.5 (m, 6H), 4.82 (s,2H), 4.10 (t, J=7 Hz, 2H), 1.7 (m, 2H), 1.25 (m, 2H), 0.8 (t, J=7 Hz,3H).

1-Butyl-2,4-diphenyl-5-(N-butyl-N-benzyl)aminomethylimidazoledihydrochloride (118). Thionyl chloride (1 ml) is added to a solution of1-butyl-2,4-diphenyl-5-hydroxymethylimidazole (0.5 g) in chloroform (10mL) and the mixture is heated to reflux for 10 minutes. The reaction isthen concentrated and dried on a vacuum pump. The crude chloride isdissolved in acetonitrile (10 mL) and N-butylbenzylamine (0.27 g, 1equiv). Potassium carbonate (1g) is added. The reaction is heated at 60°C. for 8 h, cooled and partitioned between ether and water. The etherlayer is dried (Na₂SO₄) and concentrated. The crude product is purifiedon silica (5% MeOH/CH₂Cl₂) to give the desired product as an oil. 1H NMR(CDCl3) 7.70 (d, J=5 Hz, 2H), 7.58 (d, J=4 Hz, 2H), 7.2-7.5 (m, 11H),4.15 (t, J=7 Hz, 2H), 3.77 (s, 2H), 3.52 (s, 2H0, 2.38 (t, J=7 Hz, 2H),1.6 (m, 4H), 1.2 (m, 2H), 1.05 (m, 2H), 0.8 (t, J=7 Hz, 3H), 0.73 (t,J=7 Hz, 3H). The free base is converted to the hydrochloride saltC₃₁H₃₇N₃ 2HCl ½H₂O.

C, H, N Calc: 69.78; 7.56; 7.86. Found; 69.79; 7.81; 7.46.

Example 6 Preparation ofBis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-2-phenyl-5-trifluoromethyl-3H-imidazol-4-ylmethyl)-amine(125)

4-trifluoromethyl 2-phenylimidazole (120).1,1,1-Trifluoro-3,3-dibromoacetone is added to a solution of NaOAc(11.97 g, 145 mmol) in water (40 mL). The reaction mixture is stirred at70-80° C. for 30 minutes. After cooling, the solution is added tobenzaldehyde (4.25 g, 40 mmol) in methanol (200 mL) and concentratedammonium hydroxide (50 mL) at room temperature. The mixture is stirredfor 4 h. The reaction is monitored by TLC. The reaction mixture isevaporated in vacuo to remove the organic solvent and cooled to roomtemperature. The solid is collected by filtration gave desired product120.

NMR (CDCl₃, δ ppm): 7.38-7.42 (m, 1H), 7.46 (t, J=7.2 Hz, 2H), 7.85 (d,J=1.3 Hz, 1H), 7.96-7.99 (dd, J=1.5, 7.2 Hz, 2H).

N-butyl 4-trifluoromethyl 2-phenyimidazole (121) Powdered KOH (3 mmol)is suspended in DMSO (4 mL). A solution of 120 (2 mmol) and n-BuI (4.5mmol) in DMSO (4 mL) is added and the solution is stirred overnight. Thereaction mixture is diluted with ether (80 mL) and water (80 mL). Theaqueous phase is extracted with ether (20 ml×2). Combined organic phaseare washed with water (2×100 mL), dried over MgSO₄, and concentrated invacuo to dryness to provide the product 121 as a colorless oil.NMR(CDCl₃, δ ppm): 0.88 (t, J=7.5 Hz, 3H), 1.26-1.31(m, 2H), 1.72-1.75(m, 2H), 4.00 (t, J=7.5 Hz, 2H), 7.35 (s, 1H), 7.45-7.47 (m, 3H),7.55-7.57 (m, 2H).

n-Butyl 4-trifluoromethyl 5-formyl 2-phenyimidazole (122) n-BuLi (1.6Min hexane, 30 mL) is added to a solution of 121 (10.8 g, 40.3 mmol) inanhydrous THF (100 mL) at −78° C. under N₂ over a 30 minute period Thereaction mixture is stirred at −78° C. for 1 h, followed by the followedby the addition of anhydrous DMF (5 mL), and stirred at −78° C. for 3 h.20 ml of water is added at −50° C. and the reaction mixture is dilutedwith EtOAc. Organic layer are separated and washed with H₂O and brine,and dried over MgSO₄. Concentration in vacuo to dryness provides thedesired product 122. ¹H NMR (CDCl₃, δ ppm): 0.83 (t, J=7.5 Hz, 3H)1.13-1.26 (m, 2H), 1.66-1.70 (m, 2H), 4.34 (t, J=7.5 Hz, 2H), 7.50-7.52(m, 3H), 7.53-7.59 (m, 2H), 10.0 (s, 1H).

N-butyl 4-trifluoromethyl 5-hydroxymethyl 2-phenylimidazole (123) NaBH₄is added to a solution of 122 (8.0 g, 27 mmol) in methanol (150 mL) insmall portions at 0° C. After the addition is complete, the mixture isstirred at 0° C. for an additional 30 minutes Ice (30 g) is added slowlyand die mixture is evaporated in vacuo to remove the organic solvent.Product is collected the solid by filtration, washed with water, driedin vacuo at 35° C. overnight, to give the desired product 123. ¹HNMR(CDCl₃, δ ppm): 0.83 (t, J=8.0 Hz, 3H), 1.21-1.26 (m, 2H), 1.65-1.69(m, 2H), 4.08 (t, J=8.0Hz, 2H), 4.79 (s, 2H), 7.45-7.48 (m, 3H),7.53-7.56 (m, 2H).

Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-2-phenyl-5-trifluoromethyl-3H-imidazol-4-ylmethyl)-amine(125) Mesyl chloride is added to a solution of 123 (393 mg, 1.32 mmol)and TEA (2.6 mmol) in chloroform (10 mL) at 0-5° C. The reaction mixtureis stirred at room temperature for 4 h. until the reaction complete andthen concentrated in vacuo to dryness. The residue is dissolved inacetonitrile (20 mL) and dipiperonylamine (376 mg, 1.32 mmol) and K₂CO₃(728 mg, 5.28 mmol) are added. The reaction mixture is heated underreflux overnight. The solvent is removed in vacuo, the residue isdissolved in ethyl acetate, washed with water, and dried over MgSO₄.Concentration in vacuo gives the product 125. ¹H NMR (CDCl₃, δ ppm):0.67 (t, J=7.7 Hz, 3H), 0.88-0.94 (m, 2H), 1.18-1.22 (m, 2H), 3.44 (s,4H), 3.68 (s, 2H), 4.04 (t, J=7.1 Hz, 2H), 5.92 (s, 4H), 6.73-6.74 (m,4H), 6.76 (s, 2H), 7.41-7.44 (m, 3H), 7.48-7.51 (m, 2H).

Example 7 Preparation of5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino)-methyl]-1-butyl-2-phenyl-1H-imidazole-4-carbonitrile(129)

4-Cyano2-phenylimidazole (126), 4-trifluoromethyl 2-phenylimidazole (20g, 94 mmol) is added to a 5% ammonium hydroxide solution (200 mL). Themixture is then warmed to 60-65° C. and stirred for 2 b, extracted withethyl acetate (300 ml×3), and dried over MgSO₄. Evaporation to drynessgives the desired product 126 (14g). ¹H NMR (CDCl₃, δ ppm): 7.40-7.45(m, 3H), 7.73 (s, 1H), 7.82-7.85 (m, 2H).

N-butyl 4-Cyano2-phenylimidazole (127). N-butyl 4-Cyano2-phenylimidazoleis synthesized by the procedure given for compound 121. ¹H NMR (CDCl₃, δppm): 0.73 (t, J=7.6 Hz, 3N), 1.11-1.16 (m, 2H), 1.57-1.61 (m, 2H), 3.93(t, J=7,6 Hz, 2H), 7.34-7.37 (m, 3H), 7.42-7.45 (m, 2H), 7.51 (s, 1H).

N-butyl 4-cyano-5-formyl 2-phenylimidazole (128). N-butyl4-cyano-5-formyl 2-phenyimidazole is synthesized by the procedure givenfor compound 121. ¹H NMR (CDCl₃, δ ppm): 0.82 (t, J=7.5 Hz, 3H)1.19-1.26 (m, 2H), 1.63-1.68 (m, 2H), 4.34 (t, J=7.5 Hz, 2H), 7.49-7.57(m, 5H), 9.99 (s, 1H).

Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-2-phenyl-5-cyano-3H-imidazol-4-ylmethyl)-amine(129)Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-2-phenyl-5-cyano-3H-imidazol-4-ylmethyl)-amineis synthesized by the procedure given for compound 125.

¹H NMR (CDCl₃, δ ppm): 0.68 (t, J=7.4 Hz, 3H), 0.84-0.96 (m, 2H),1.18-1.26 (m, 2H), 3.49 (s, 4H), 3.68 (s, 2H), 3.99 (t, J=7. Hz, 2H),5.90 (s, 4H), 6.73 (s, 4H), 6.77 (s, 2H), 7.44 (brs, 5H).

Example 8 Preparation ofBis-benzo[1,3]dioxol-5-ylmethyl-[3-butyl-5-(5-methyl-thiophen-2-yl)-2-phenyl-3H-imidazol-4-ylmethyl]-amine

Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-2-phenyl-3H-imidazol-4-ylmethyl)-amine(136) is synthesized via the procedure given for compound 125.

¹H NMR (CDCl₃, δ ppm): 0.69 (t, J=7.4 Hz, 3H), 0.95-1.00 (m, 2H),1.22-1.31 (m, 2H), 3.44 (s, 4H), 3.54 (s, 2H), 3.98 (t, J=7. Hz, 2H),5.91 (s, 4H), 6.73 (s, 4H), 6.79 (s, 2H), 7.01 (s, 1H), 7.38-7.42 (m,3H), 7.51-7.54 (m, 2H).

Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-2-phenyl-5-bromo-3H-imidazol-4-ylmethyl)-amine(137). ¹H NMR (CDCl₃, δ ppm): 0.69 (t, J=7.4 Hz, 3H), 0.89-0.96 (m, 2H),1.24-1.28 (m, 2H), 3.45 (s, 4H), 3.54 (s, 2H), 4.00 (t, J=7. Hz, 2H),5.90 (s, 4H), 6.73 (s, 4H), 6.77 (s, 2H), 7.38-7.42 (m, 3H), 7.48-7.51(m, 2H).

Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-2-phenyl-5-bromo-3H-imidazol-4-ylmethyl)-amine(138). ¹H NMR (CDCl₃, δ ppm): 0.69 (t, J=7.4 Hz, 3H), 0.89-0.96 (m, 2H),1.24-1.28 (m, 2H), 2.52 (s, 3H), 3.48 (s, 4H), 3.80 (s, 2H), 4.06 (t,J=7. Hz, 2H), 5.91 (s, 4H), 6.73 (m, 5H), 6.77 (s, 2H), 7.17 (d, J=3.3Hz, 1H), 7.38-7.46 (m, 3H), 7.55-7.58 (m, 2H).

Example 9 Preparation of 4-Fluoroimidazole Compounds

1-Butyl-2-phenyl-5-hydroxymethylimidazole (139). Sodium borohydride(1.135 g, 30 mmol) is added to a solution of aldehyde 138 (6.849 g, 30mmol) in 100 ml of methanol cooled to 0° C. The resulting solution isstirred at 0° C. for 30 min, evaporated and the residue dissolved in 150ml of ethyl acetate, washed with water and brine, dried over Na₂SO₄,concentrated and taken to dryness under high vacuum to give the product139 as an oil. MS (+VE) m/z 231 (M+1).

1-Butyl-2-phenyl-4-bromo-5-hydroxy-methylimidazole (140). N-bromosuccinimide (3.56 g, 20 mmol) is added to a solution of alcohol 139(4.60 g, 20 mmol) in 100 ml of anhydrous acetonitrile cooled to 0° C.,in portions over 15 minutes. The resulting mixture is stirred at 0° C.for 60 min, water is added to quench the reaction, the acetonitrile isevaporated, and the residue dissolved in 100 ml of ethyl acetate, washedwith water and brine, and dried over Na₂SO₄. The solvent is evaporatedand the residue purified by silica gel flash chromatography(hexanes/ethyl acetate, from 6:1 to 3:1) to give 3.15 g of product 140.¹H NMR (300 MHz, CDCl₃) δ 7.48-7.56 (2H, m), 7.40-7.47 (3H, m), 4.67(2H, s), 4.07 (2H, t, J=7.60 Hz), 1.65 (2H, m), 1.24 (2H, m), 0.83 (3H,t, J=7.5 Hz). MS (+VE) m/z 309 (M⁺), 311 (M+2).

Compound (141). 3,4-Dihydro-2H-pyran (1.41 g, 16.8 mmol, 5 eq.)is addedto a solution of alcohol 140 (1.04 g, 3.36 mmol) in 20 ml of anhydrousdichloromethane cooled to 0° C., followed by addition ofp-toluenesulfonic acid monohydrate (10 mg). The mixture is stirred atroom temperature overnight. The solution is diluted with 20 ml of etherand washed with a solution made up of 5 ml of NaHCO₃-5 ml brine-10 mlwater. The aqueous phase is extracted with ether and the combinedorganic solutions are dried with Na₂SO₄. The solvent is evaporated andthe residue purified by silica gel flash chromatography (hexanes/ethylacetate, from 8:1 to 5:1) to give compound 141 as a sticky oil. ¹H NMR(300 MHz, CDCl₃) δ 7.54-7.58 (2H, m), 7.72-7.47 (3H, m), 4.75 (1H, d,J=13 Hz), 4.73 (1H, m), 4.58 (1H, d, J=13 Hz), 4.06 (2H, m), 3.94 (1H,m), 3.61 (1H, m), 1.45-1.88 (8H, m), 1.23 (2H, m), 0.83 (3H, t, J=7.5Hz). MS (+VE) m/z 393 (M⁺), 395 (M+2).

Compound (142). A solution of butyl lithium in hexanes (1.6M, 1.02 ml,1.64 mmol) is added to a solution of compound 141 (537 mg, 1.37 mmol) in10 ml of anhydrous THF at −78 CC under nitrogen. The resulting mixtureis stirred at −78° C. for 60 min; a solution ofN-fluorobenzenesulfonimide (516 mg, 1.64 mmol) in 10 ml of THF is thenadded dropwise. The resulting solution is stirred at −78° C. for 30 min,warmed to room temperature, and then stirred overnight. 10 ml ofsaturated NaHCO₃ is added to quench the reaction. The mixture is dilutedwith 50 ml of ethyl acetate, the organic layer is separated, washed withwater and brine, and dried over Na₂SO₄. Concentration and purificationthrough silica gel chromatography (hexanes/ethyl acetate, from 8:1 to5:1) affords compound 142. ¹H NMR (400 MHz, CDCl₃) δ 7.52-7.55 (2H, m),7.37-7.44 (3H, m), 4.70 (1H, d, J=13 Hz), 4.69 (1H, m), 4.51 (1H, d,J=13 Hz), 3.95-4.07 (2H, m), 3.88 (1H, m), 3.56 (1H, m), 1.48-1.82 (8H,m), 1.22 (2H, m) 0.82 (3H, t, J=7.2 Hz). MS (+VE) m/z 333 (M+1).

1-Butyl-4-fluoro-5-hydroxymethyl-2-phenylimidazole (143).1-Butyl-2-phenyl-4-fluoro-5-hydroxymethylimidazole 142 (100 mg, 0.30mmol) is dissolved in a solution made up of 1.0 ml acetic acid-1.0 mlTHF-1.0 ml water. The solution is heated to 55-60° C. and stirred for 2h. The acetic acid and THF are evaporated, the residue basified withodium hydroxide solution, extracted with ethyl acetate, washed withwater and brine, and dried over Na₂SO₄. The product is concentrated andtaken to dryness under high vacuum to give compound 143. MS (+VE) m/z249 (M+1).

Benzo[1,3]dioxol-5-ylmethyl-(3-butyl-5-fluoro-2-phenyl-3H-imidazol-4-ylmethyl)-amine(144). Compound 143 (76 mg, 0.30 mmol) is dissolved in 2 mldichloromethane and cooled to 0° C. Thionyl chloride (0.05 mL) is addedand the resulting solution is stirred at room temperature for 2 h. Thesolvent and excess thionyl chloride are evaporated. The residue isdissolved in 1.0 ml DMF and added to a solution of piperonyl amine (227mg, 1.5 mmol) in DMF (2 mL) containing 100 mg potassium carbonate. Theresulting mixture is stirred at room temperature for 2 h, then dilutedwith 20 ml of ethyl acetate, washed with water and brine, dried, andconcentrated. The resulting residue is purified with silica gelchromatography (hexanes/ethyl acetate, from 2:1 to 1:1) to providecompound 144. MS (+VE) m/z 382 (M+1).

Benzo[1,3]dioxol-5-ylmethyl-(3-butyl-5-fluoro-2-phenyl-3H-imidazol-4-ylmethyl)(3ethoxy-benzyl)-amine (145) Compound 144 (0.079 mmol) is dissolved in 2ml 1,2-dichloroethane. 3-Ethoxybenzaldehyde (28 mg, 2.0 eq) is addedfollowed by one drop of acetic acid. The solution is stirred at roomtemperature for 2 hr; sodium triacetoxyborohydride (50 mg, 0.236 mmol,3.0 eq.) is then added. The resulting mixture is stirred at roomtemperature overnight. The reaction mixture is diluted with 10 ml ofdichloromethane, washed with water and brine, dried, and concentrated.The residue is purified by silica gel flash chromatography(hexanes/ethyl acetate, from 8:1 to 4:1) to afford compound 145¹H NMR(400 MHz, CDCl₃) δ 7.47-7.52 (2H, m), 7.38-7.4 (3H, m), 7.21 (1H, t, J=8Hz), 6.82-6.90 (3H, m), 6.7-6.78 (3H, M), 5.93 (2H, s), 4.01 (2H, q,t=7.2 Hz), 3.92 (2H, t, J=7.6 Hz) 3.52 (2H, s), 3.51 (2H, s) 3.48 (2H,s), 1.41 (3H, t, J=6.8 Hz), 1.34 (2H, m), 0.99 (2H, m), 0.71 (3H, t,J=7.2 Hz). MS (+VE) m/z 516.3 (M+1).

Example 10 Preparation of cycloalkylimidazole compounds:4-{[butyl(1-butyl-2-phenyl(4,5,6-trihydrocyclopenta[3,2-D]imidazol-6-yl))amino]methyl}-3-chlorophenol(156)

N-(n-butyl)-benzamidine (150). 7 ml of triethylamine is added to asolution of methyl benzimidate hydrochloride (12g 0.07 mole) indimethylformamide (DMF, 20 mL) at 0° C. After 2 h the reaction isfiltered to remove triethylamine hydrochloride. 1-Butylamine (3.69 g) isadded to the filtrate and the mixture is heated to 60° C. for 6 hours.After cooling the mixture is partitioned between ethyl acetate andwater. The organic layer is washed with brine, dried over sodium sulfateand concentrated to provide the amidine as a yellow oil. ¹H NMR (CDCl₃)7.55 (m, 2H), 7.4 (m, 3H), 3.37 (bm, 2H) 1.62 (m, 2H), 1.42 (m, 2H),0.95 (t, J=7 Hz, 5H).

2-Bromo-3-methoxycyclopentenone (151) is prepared via the method ofCurran et al JACS, vol 112, page 5601. N-Bromosuccinimide (18.2 g) isadded to a suspension of 1,3-cyclopentanedione (10g) in chloroform (700mL). The mixture is refluxed for 2 h, cooled and concentrated. Methanol(700 mL) and p-toluenesulfonic acid (1 g) are added and the solution isrefluxed overnight. The mixture is concentrated to 100 ml, diluted withmethylene chloride (500 ml), and poured into water. The aqueous layer isdiscarded and the organic layer is washed with water (3×100 mL), dried(Na₂SO₄) and concentrated. The residue is crystallized from ethylacetate to give 151 as tan crystals (1.67 g).

1-Butyl-2-phenyl-4,5-dihydrocyclopenty[1,2-d]imidazol-6-one (152). Solidpotassium carbonate (3.32 g, 24 mmol) is added to a mixture of amidine150 (3.52 g, 20 mmol) and enone 13 (4.58 g, 24 mmol) in chloroform (40mL) and water (5 mL) The resulting mixture is refluxed overnight. Aftercooling, the mixture is washed with water, dried (Na₂SO₄) andconcentrated. Purification on silica gel eluting with 25% ethylacetate/hexane gives the desired product 152 (3.0 g) LC-MS (M⁺+1): 255.¹H NMR (δ, CDCl₃): 0.84 (t, J=7.6 Hz, 3H), 1.23 (dt, J=7.0, 7.6 Hz, 2H),1.81 (m, 2H), 2.95 (m, 4H), 4.13 (t, J=7.6 Hz, 2H) 7.5-7.45 (m, 3H),7.76-7.6 (m, 2H) ppm.

1-Butyl-2-phenyl-4,5-dihydrocyclopenty[1,2-d]imidazol-6-ol (153). Sodiumborohydride (1.5 equiv) is added to a solution of 152 (2.68 g) inmethanol (20 mL) and the mixture is stirred overnight. The mixture isconcentrated, diluted with chloroform, and washed with 0.5 N NH₄Clsolution. The organic layer is dried (Na₂SO₄) and concentrated toprovide the desired product 153. LC-MS (M+1) 257.

Butyl(1-butyl-2-phenyl-4,5,6-trihydrocyclopentyl[3,2-d]imidazol-6-yl))amine(155). Compound 153 (2g) is dissolved in chloroform (20 mL) and thionylchloride (5 mL); the resulting solution is stirred at room temperatureovernight. The solvent and excess thionyl chloride are evaporated andthe crude chloride 154 dissolved in n-butylamine (10 mL). After 2 h, theexcess butylamine is evaporated, the residue dissolved in ethyl acetateand the organic solution washed with 5% NaOH solution aid water. Theorganic layer is dried and concentrated. The organic residue is purifiedby column chromatography on silica gel eluting with 10% CH₃OH in CHCl₃to provide the desired secondary amine 155. LC-MS (M+1) 312 ¹H NMR(chemical shift, CDCl₃): 0.83 (t, J=72 z, 3H), 0.9 (t, J=7.2 Hz, 3H),1.23 (q, J=7.2 Hz, 2H), 1.35 (q, J=7.2 Hz, 2H), 1.46 (m, 2H), 1.70 (m,2H), 2.24 (m, 1H), 2.55-2.66 (m, 4H), 2.73-2.80 (m, 2H), 3.97-4.04 (m,2H), 4.30 (d, J=5.6 Hz, 1H), 7.37-7.44 (m, 3H), 7.55-7.57 (m, 2H).

4-{[Butyl (1-butyl-2-phenyl(4,5,6-trihydrocyclopenta[3,2-d]imidazol-6-yl))amino]methyl}-3-chlorophenol(156). Sodium triacetoxyborohydride (100 mg) is added to a solution of155 (50 mg) in 1,2-dichloroethane (2 mL) and2-chloro-4-hydroxybenzaldehyde (30 mg) is added. The resulting mixtureis allowed to stir overnight. After washing with 0.5 ammonium chloridesolution, the organic layer is dried (Na₂SO₄) and concentrated.Purification using preparative thin layer chromatography eluting with 5%CH₃OH/CHCl₃ provides the desired product 156 as an oil (21 mg). LC-MS(M+1) 452, (M−1) 450. ¹H NMR (chemical shift, CDCl₃): 0.74 (t, J=7.2 Hz,3H), 0.83 (t, J=7.2 Hz, 3H), 1.11 (q, J=7.2 Hz, 2H), 1.21-1.33 (m, 2H),1.41-1.51 (m, 4H), 2.34-2.44 (m, 3H), 2.51-2.57 (m, 1H), 2.60-2.67 (m,1H), 2.69-2.75 (m, 1H), 3.38 (d, J=7.6 Hz, 1H), 3.47 (d, J=13.6 Hz, 1H),3.65 (d, J=13.6 Hz, 1H), 3.78-3.96 (m, 1H), 6.62 (dd, J=8,2 Hz, 1H),6.78 (d, J=2 Hz, 1H), 7.07 (d, J=8 Hz, 1H), 7.35-7.41 (m, 3H), 7.45-7.48(m, 2H).

Example 11 Preparation of2-Phenyl-4-(N,N-di{2H-benzo[3,4-D]-1,3-dioxolan-5-ylmethyl})aminomethyl-3-butylpyridine(161)

4-Phenyl-5-butyloxazole (157). A mixture of α-bromohexanophenone (25.5g, 0.1 mole), ammonium formate (22 g, 0.35 mole) and formic acid (110mL) is refluxed with stirring for 3 hours. The reaction mixture ispoured onto ice, made basic with 10 N NaOH, and extracted with ether.The organic layer is washed with water, dried over sodium sulfate, andconcentrated. The crude product is purified by flash chromatography onsilica gel eluting with 20% ethyl acetate in hexane to provide thedesired compound as an oil. ¹H NMR (δ, CDCl₃, 400 MHz) 7.55 (m, 2H),7.40 (s, 1H), 7.34 (dd, J=7,7 Hz, 2H), 7.22 (dd, J=7, 7 Hz, 1H), 2.74(m, 2H), 1.6 (m, 2H), 1.30 (m, 2H), 0.84 (t, J=7 Hz, 3H) ppm.

2-Phenyl-3-butylisonicotinic acid (158). A mixture of4-phenyl-5-butyloxazole (12, 5 g, 25 mmol) and maleic acid (3.5 g, 30mmol) is heated at 100° C. for 30 minutes After cooling, the semisolidmass is triturated with ether and the solid collected by filtration. ¹HNMR (δ, CDCl₃, 400 MHz) 11.68 (brs, 1H), 8.72 (d, J=6.0 Hz, 1H), 7.73(d, J=5.6 Hz, 1H), 7.48-7.51 (m, 2H), 7.42-7 4 (m, 2H), 6.25 (s, 1H),2.86 (d, J=7.6 Hz, 21, 1.36 (m, 2H), 1.11 (dt, J=7.6, 7.2 Hz, 21, 0.68(t, J=7.6 Hz, 3H). MS (M+1): 256, (M−1) 254.

2-Phenyl-4-hydroxymethyl-3-butylpyridine (159). Lithium aluminum hydride(4 ml of 1M in tetrahydrofuran) is added to a solution of2-phenyl-3-butylisonicotinic acid (510 mg, 2 mmol) in tetrahydrofuran(20 mL). The reaction is stirred overnight and then quenched with 5 mlof 15% aqueous NaOH. The resulting mixture is extracted with ether,dried (Na₂SO₄), and concentrated to provide the desiredhydroxymethylpyridine as an oil. LC-MS (M+1): 242; ¹H NMR (δ, CDCl₃)8.35 (1H, d, J=5.2 Hz), 7.30-7.39 (6H, m), 4.59 (2H, s), 2.43 (2H, t,18.0 Hz), 1.23 (2H, m), 1.13 (2H, m), 0.70 (3H, t, J=7.2 Hz).

2-Phenyl-4-(N-{2H-benzo[3,4-d]-1,3-dioxolan-5-ylmethyl})aminomethyl-3-butylpyridine(160). Thionyl chloride (200 mg, 1.67 mmol) is added to a solution of2-phenyl-4-hydroxymethyl-3-butylpyridine (400 mg 1.66 mmol) in pentenestabilized chloroform (8 mL) and the mixture is heated to 50° C. for 2hours. The resulting mixture is cooled, washed with saturated sodiumbicarbonate solution, dried (Na₂SO₄) and concentrated. The resultingcrude chloride is taken up in dimethylformamide (10 mL) and addeddropwise to a refluxing solution of piperonylamine (1.0 g, 4 equiv) indimethylformamide (30 mL) containing 3g of powdered potassium carbonate.After the addition is complete, the resulting mixture is refluxed for anadditional 3 h, cooled and partitioned between water (200 mL) and ether(100 mL). The etherlayer is washed 2 times with water, dried (Na₂SO₄),and concentrated. The resulting material is purified by chromatographyon silica eluting with 10% CH₃OH/CHCl₃ to give the desired secondaryamine 160. LC-MS (M+1): 375.3; ¹H NMR (δ, CDCl₃); 0.73 (3H, t, J=7.2Hz), 1.15 (2H, m J=7.2 Hz), 1.30 (2H, m), 2.58 (2H, t, J=8.0 Hz) 3.79(2H, s), 3.83 (2H, s), 5.93 (2H, s), 6.75-6.82 (2H, m), 6.89 (1H, d,J=1.2 Hz), 7.36-7.42 (6H, m), 8.45 (1H, d, J=4.8 Hz) ppm.

2-Phenyl-4-(N,N-di{2H-benzo[3,4-d]-1,3-dioxolan-5-ylmethyl})aminomethyl-3-butylpyridine(161). Piperonal (30 mg) is added to a solution of 160 (38 mg) indichloroethane (5 mL). The resulting mixture is stirred for 3 h afterwhich time sodium triacetoxyborohydride (150 mg) is added in one portionand the resulting mixture is stirred overnight. The reaction mixture isquenched with 10% ammonium hydroxide solution (5 mL). The organic layeris washed with water and extracted with 1N HCl solution. The acidicextract is made basic with 1N NaOH solution and extracted withchloroform. The organic extract is dried (Na₂SO₄) and concentrated. Theresulting oil is purified on preparative thin layer chromatographyeluting with 10% CH₃OH/CHCl₃ to give the desired tertiary amine 161 asan oil. LC-MS (M+1): 509.4; ¹H NMR (δ, CDCl₃): 0.71 (3H, t, J=7.2 Hz),1.10 (2H, m, J=7.2 Hz), 2.60 (2H, t, J=8.0 Hz), 3.48 (4H, s) 3.58 (2H,s), 5.94 (4H, s), 6.75 (1H, d, J=8.0 Hz), 6.80 (1H, dd, J=0.8, 8.0 Hz),6.91 (1H, d, J=0.8 Hz), 7.36-7.43 (5H, m), 7.56 (1H, d, J=5.2 Hz), 8.47(1H, d, J=5.2 Hz) ppm.

Example 12 Preparation of an Arylpyrazole:1,3-diphenyl-4-(N-{2H-benzo[3,4-D]-1,3-dioxolan-5-ylmethyl}-N-butylamino)methyl-5-propylpazole(167)

N′-Phenyl-N-phenylhydrazone (162). Benzaldehyde (9.81 g, 9.25 mmol) isadded at 0-5° C. to a solution of phenyl hydrazine (10 g, 9.25 mmol) inethanol (100 mL). A cream colored solid forms and the reaction mixtureis allowed to stand for 2 hours. The solid is collected by filtration,washed with ice-cold ethanol and dried under vacuum to provide thedesired compound, 162;LC-MS m/z 197.2.

Ethyl 1,3-diphenyl-5-propylpyrazole-4-carboxylate (164). A mixture of162 (5 g, 25.5 mmol) and ethyl butyrylacetate (20.2 g 128 mmol) and acatalytic amount of zinc chloride is heated at 125° C. under an airatmosphere for 3 hours. The reaction vessel is fitted with a short pathdistillation head and excess ethyl butyrylacetate is distilled awayunder vacuum. The resulting material is purified by columnchromatography on silica eluting with 10% ethyl acetate in hexanes toprovide the desired ester 164 as a yellow oil which crystallizes uponstanding. Recrystallization from diisopropyl ether provides a whitesolid. MS (M+1): 335.2.

1,3-Diphenyl-4-hydroxymethyl-5-propylpyrazole (165). 4 ml of a 1Msolution of lithium aluminum hydride in tetrahydrofuran is added to asolution of ester 164 (670 mg, 2 mmol) in tetrahydrofuran (20 mL). Thereaction is stirred overnight and then quenched with 5 ml of 15% aqueousNaOH. The resulting mixture is extracted with ether, dried (Na₂SO₄), andconcentrated to provide the desired hydroxymethylpyrazole as an oil,LC-MS (M+1): 293.3; ¹H NMR (δ, CDCl₃) 7.86 (dd, J=8.4 Hz, 2H), 7.34-7.52(m, 8H), 4.65 (s, 2H), 2.72 (t, J=8.0 Hz, 2H), 1.52 (m, 2H), 0.87 (t,J=7.6 Hz, 3H).

[(1,3-Diphenyl-5-propylpyrazol-4-yl)methyl]butyl amine (166). Thionylchloride (1 mL) is added to a solution of 165 (289 mg) in pentenestabilized chloroform (8 mL) and the mixture heated to 60° C. for 2hours. The resulting mixture is cooled, washed with saturated sodiumbicarbonate solution, dried (Na₂SO₄), and concentrated. The resultingcrude chloride is taken up in dimethylformamide (3 mL) and addeddropwise to a solution of butylamine (1.0 g) in dimethylformamide (10mL) containing 2g of powdered potassium carbonate. After the addition iscomplete, the resulting mixture is stirred for an additional 3 h andpartitioned between water (20 mL) and ether (10 mL). The ether layer iswashed 2 times with water, dried (Na₂SO₄), and concentrated. Theresulting material is purified by chromatography on silica eluting with10% CH₃OH/CHCl₃ to give the desired secondary amine 166. LC-MS (M+1):348.3; ¹H NMR (δ, CDCl₃), 7.87 (dd, J=8.0, 1.6 Hz, 2H), 7.32-7.48 (m,1H), 3.77 (s, 2H), 2.70 (m, 4H), 1.48 (m, 4H), 1.34 (m, 2H), 0.91 (t,J=7.6 Hz, 3H), 0.87 (t, J=7.6 Hz, 3H) ppm.

1,3-Diphenyl-4-(N-{2H-benzo[3,4d]-1,3-dioxolan-5-ylmethyl}-N-butylamino)methyl-5-propylpyrazole(167). Piperonal (30 mg) is added to a solution of 166 (35 mg) indichloroethane (5 mL). The resulting mixture is stirred for 3 h afterwhich time sodium triacetoxyborohydride (150 mg) is added in one portionand the resulting mixture is stirred overnight. The reaction mixture isquenched with 10% ammonium hydroxide solution (5 mL). The organic layeris washed with water and extracted with 1N HCl solution. The acidicextract is made basic with 1N NaOH solution and extracted withchloroform. The organic extract is dried (Na₂SO₄) and concentrated. Theresulting oil is purified on preparative thin layer chromatographyeluting with 10% CH₃OH/CHCl₃ to give the desired tertiary amine (167) asan oil. LC-MS (M+1): 482.5; ₁H^(NMR) (δ, CDCl₃): 7.87 (d, J=7.2 Hz, 2H),7.47 (d, J=4.4 Hz, 4H), 7.33-7.43 (m, 4H), 6.77 (s, 1H), 6.70 (s, 2H),5.92 (s, 2H), 3.56 (s, 2H), 3.42 (s, 2H), 2.74 (t, J=8.0 Hz, 2H), 2.37(t, J=7.2Hz, 2H), 1.42 (m, 4H), 1.21 (m, 2H), 0.83 (t, J=7.6 Hz, 3H),0.81 (t, J=7.2 Hz, 3H) ppm.

Example 13 Preparation of an Aryltriazole:Benzo[1,3]dioxol-5-ylmethyl-butyl-(4-butyl-5-phenyl-4H-[1,2,4]triazol-3-ylmethyl)-amine(171)

N-butyl-oxalamic acid ethyl ester (168). Ethyl oxalyl chloride (1.1 eq.)is added slowly to a mixture of n-butylamine (7.31 g, 0.1 mol) andtriethylamine(1.2 eq.) in DCM(60 mL) at 0° C., stirred at 0° C. for 2hours. The reaction mixture is quenched with water, washed with 2N NaOH,2N HCl and brine, dried with anhydrous Na₂SO₄, and concentrated. Theresidue is taken up in ether and the solid removed. The filtrate isconcentrated and the residue is taken up in ether, and filtered toremove a slight amount of solid. The filtrate is concentrated to givethe product (168). ¹HNMR(CDCl₃): δ=4.32 (2H, q, —OCH₂—), 3.32(2H, q,—NHCH₂—), 1.30-1.60(7H, m), 0.92(3H, t, —OCH₂CH₃)

4-Butyl-5-phenyl-4H-[1,2,4]triazole-3-carboxylic acid butyl ester (169).Starting material (1.68) is taken up in 35 ml thionyl chloride, refluxedfor 2.5 hours, cooled to room temperature, and the excess thionylchloride removed. The residue is taken up in 50 ml toluene, benzoichydrazide(1.0 eq.) is added, the mixture is stirred at room temperatureovernight and then refluxed for 2.5 hours. The reaction mixture iscooled to room temperature, mixed with water, and washed with water andbrine. Purification by column chromatography with hexane/ethyl acetategives the product (169).

¹HNMR(CDCl₃): δ=7.52-7.60(5H, m, phenyl-H), 4.50(2H, q, J=7.2 Hz, —OCH₂CH₃), 4.34(2H, t, J=7.5 Hz, N—CH₂-n-C₃H₇) 1.60-1.80 (2H, m, —CH₂—),1.47(3H, t, J=7.2 Hz,—CH₃), 1.18-1.38(2H, m, —CH₂—), 0.83(3H, t, J=7.5Hz, —CH₃)

(4-Butyl-5-phenyl-4H-[1,2,4]triazol-3-yl)-methanol (170).4-Butyl-5-phenyl-4H-[1,2,4]triazole-3-carboxylic acid butyl ester (169)(1.38 g, 5 mmol) is taken up in 50 ml anhydrous THF. LAH is added (3eq.). The reaction is refluxed for 12 hours and then quenched carefullywith water. Purification by column with 2.5% MeOH/DCM gives the desiredproduct (170). ¹HNMR(CDCl₃): δ=7.40-7.60(5H, m, phenyl-H), 4.88(2H, s,—CH₂ OH), 4.26(1H, br, —OH), 4.10 (2H, t, J=7.8 Hz, —CH₂—), 1.58-1.70(2H, m, —CH₂—), 1.08-130(2H, m, —CH₂—), 0.82 (3H, t, J=7.5HZ, —CH₃)

Benzo[1,3]dioxol-5-ylmethyl-butyl-(4-butyl-5-phenyl-4H-[1,2,4]triazol-3-ylmethyl)-amine(171) (4-Butyl-5-phenyl-4H-[1,2,4]triazol-3-yl)-methanol (170) (174 mg,0.75 mmol) is taken up in 5 ml anhydrous DCM, triethylamine (1.2 eq.) isadded, MsCl(1.1 eq.) is added at 0° C., and the reaction is then stirredat room temperature for 2 hours, concentrated, and the residue dried onhigh vacuum for 2 hours. The residue is mixed with amine(1.0 eq.) andK₂CO₃ (2.0 eq.) in 5 ml anhydrous CH₃CN and refluxed for 15 hours. Thereaction mixture is filtered and washed with ethyl acetate. Purificationby column chromatography with hexane/ethyl acetate yields the desiredproduct (171). Treatment with 1.0M HCl in ether gives a white solid HClsalt. ¹HNMR(For free amine, CDCl₃): δ=7.40-7.60(5H, m, phenyl-H),6.79(1H, s, phenyl-H), 6.74(1H, s, phenyl-H), 6.73 (1H, s, phenyl-H),5.90(2H, s, —OCH₂O—), 3.98 (2H, t, J=7.6 Hz, triazole-N—CH₂—), 3.75 (2H,s, triazole-CH₂—N—), 3.50 (s, 2H, phenyl-CH₂N—), 2.49(2H, t, J=7.2 Hz,—CH₂-nC₃H₇), 1.40-1.58(2H, m, —CH₂—), 1.20-1.40(4H, m, —CH₂—), 0.84 (3H,t, J=7.2 Hz, —CH₃), 0.72(3H, t, J=7.2 Hz, —CH₃) LC-MS: RT=2.76 min, M+1:421.21

Example 14 Preparation of a Mixture of 5-ArylPyrazoles:Benzo[1,3]dioxol-5-ylmethyl-butyl-(4-butyl-1-methyl-5-phenyl-1H-pyrazol-3-ylmethyl)-amineandbenzo[1,3]dioxol-5-ylmethyl-butyl-(4-butyl-2-methyl-5-phenyl-1H-pyrazol-3-ylmethyl)-amine(179).

3-Benzoyl-2-oxo-heptanoic acid ethyl ester (172). Diethyl oxalate(7.31G, 0.05 mol) is added to freshly made sodium ethoxide(1.05 eq.) inethanol. Hexanophenone(8.81g, 0.05 mol) is added dropwise, and theresulting mixture is stirred at room temperature overnight. Afterconcentration the residue is partitioned between 3N HCl and ethylacetate, extracted with ethyl acetate. Combined organic layers arewashed with brine and dried with anhydrous Na₂SO₄. Purification bycolumn chromatography with hexane/ethyl acetate gives the product (172).

4-Butyl-5-phenyl-2H-pyrazole-3-carboxylic acid ethyl ester (173).Diketone and hydrazine hydrochloride (1.05 eq.) are taken up in 50 mlethanol and refluxed overnight. Purification by column with hexane/ethylacetate provides the product (173).

¹HNMR(CDCl₃): δ=10.6 (1H, br, pyrazole-NH), 7.40-7.60 (5H, m, phenyl-H),4.42 (2H, q, J=7.2 Hz, —COOCH₂—), 2.83 (2H, t, J=7.8 Hz, pyrazole-CH₂—)1.20-1.70 (4H, m, —CH₂CH₂—), 0.89 (3H, t, J=7.2Hz, —Cl₃)

4-Butyl-1-methyl-5-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester(175) and 4-Butyl-2-methyl-5-phenyl-TH-pyrazole-3-carboxylic acid ethylester (174). Starting material (173) (795 mg, 2.92 mmol) is dissolved in30 ml anhydrous DMF. Potassium carbonate (3 eq.) is added followed bythe addition of iodomethane (5 eq.). The resulting mixture is stirred atroom temperature for 15 hours, until TLC shows the reaction is complete.The reaction is diluted with water and extracted with ethyl acetate. Thecombined organic layers are washed with brine and dried with anhydrousNa₂SO₄. Purification by column chromatography with hexane/ethyl acetategives the 1-methyl substituted (175) and 2-methyl substituted products(174).

1-methyl substituted pyrazole:

¹H NMR(CDCl₃): δ=7.50-7.60 (2H, m, phenyl-H), 7.30-7.50 (3H, m,phenyl-H), 4.40 (2H, q J=7.2 Hz, —COOCH₂—), 4.18 (3H, s, —NCH₃), 2.77(2H, t, J=7.8 Hz, pyrazole-CH₂—), 1.30-1.60 (7H, m, —CH₂CH₂CH₃), 0.89(3H, t, J=7.2 Hz, —CH₃)

2-methyl substituted pyrazole:

¹H NMR(CDCl₃): δ=7.40-7.60 (3H, m, phenyl-H), 7.20-7.30 (2H, m,phenyl-H), 4.43 (2H, q, J=7.2 Hz, —COOCH₂—), 3.78 (3H, s, —NCH₃), 2.59(2H, t, J=7.8 Hz, pyrazole-CH₂—), 1.38-1.50 (5H, m, —CH₂ and —CH₃),1.18-1.30 (2H, m, —CH₂—), 0.79 (3H, t, J=7.2 Hz, —CH₃)

(4-Butyl-1-methyl-5-phenyl-1H-pyrazol-3-yl)-methanol (177). 1-methylsubstituted pyrazole compound (175) (380 mg) is dissolved in 30 mlanhydrous THF.1.0 M DIBAL-H (13 ml, ˜10 eq.) is added dropwise at −78°C. The resulting mixture is warmed naturally to room temperature andstirred overnight. The reaction is quenched with saturated Na₂SO₄. Theresulting mixture is filtered and dried with anhydrous Na₂SO₄.Concentration provides the crude product (177). ¹H NMR(CDCl₃):δ=7.50-7.60 (2H, m, phenyl-H), 7.30-7.50 (3H, m, phenyl-H), 4.63 (2H, d,—CH₂OH), 3.95 (3H, s, —NCH₃), 2.58 (2H, t, pyrazole-CH₂—), 1.30-1.60(4H, m, —CH₂CH₂—) 0.90 (3H, t, —CH₃) LC-MS: RT=2.57 min, M+1: 245.23

Benzo[1,3]dioxol-5-ylmethyl-butyl-(4-butyl-2-methyl-5-phenyl-1H-pyrazol-3-ylmethyl)-amine(179). 1-methyl substituted pyrazole alcohol (177) (110 mg) is dissolvedin anhydrous DCM (4 mL) and triethylamine (1.2 eq.) is added. MsCl isadded at 0° C. and the mixture is stirred at room temperature for 2hours, concentrated, and dried on high vacuum for 30 minutes The residueis dissolved in 5 ml anhydrous CH₃CN followed by the addition of amine(1.2 eq.) and potassium carbonate (5 eq.). The resulting mixture isrefluxed for 12 hours. The reaction solution is filtered and washed withethyl acetate. Purification by column chromatography with hexane/ethylacetate provides product (179). Treated with 2M HCl in ether to give awhite solid. ¹H NMR(For free amine, CDCl₃): δ=7.58-7.60 (2H, m,phenyl-H), 7.26-7.40 (3H, m, phenyl-H), 6.81 (1H, s, phenyl-H), 6.74(2H, s, phenyl-H), 5.94 (2H, s, —OCH₂—), 3.87 (3H, s, —NCH₃), 3.48 (2H,s, pyrazole-CH₂—), 3.42 (2H, s, —CH₂Ph), 2.55 (2H, t, J=8.0 Hz,—NCH₂—C₃H₇) 2.37 (2H, t, J=7.2 Hz, pyrazole-CH₂—), 1.20-1.60 (8H, m,4X(—CH₂—)), 0.78-0.90 (6H, m, 2X(—CH₃))

LC-MS: RT=2.89 minutes, M+1: 434.28

Example 15 Preparation ofbenzo[1,3]dioxol-5-ylmethyl-butyl-(5-butyl-3-chloro-6-phenyl-pyridazin-4-ylmethyl)-amine(180)

2-Bromo-1-phenyl-hexan-1-one. CuBr₂ (26.6 g, 119.2 mmol) is added insmall portions to a solution of 1-phenyl-hexan-1-one (105 g, 59.6 mmol)in CHCl₃ (80 mL) and EtOAc (80 mL) of over a period of 1 h while thetemperature maintained at 75-80° C. Heating is continued for 6 h untilthe green color disappears. The solid is filtered and washed with EtOAc(80 mL). The combined filtrate is evaporated and the residue isdissolved in EtOAc (200 mL), washed with water (200 mL) and brine (200mL), and dried over Na₂SO₄. Evaporation of the solvent in vacuo providesa light yellow oil. LC-MS (M+1) 255. ¹H NMR (δ, CDCl₃) 7.92-8.07 (m,2H), 7.40-7.61 (m, 3H), 5.13 (t, J=7.2 Hz, 1H), 2.02-2.23 (m, 2H),1.33-1.57 (m, 4H), 0.92 (t, J=7.4 Hz, 3H).

2-(1-Benzoyl-pentyl)-malonic acid dimethyl ester. Small portions of NaH(60%, 7.92 g, 198 mmol) are added to a solution of dimethyl malonate(22.6 ml, 198 mmol) in DMSO (100 mL) at 0° C. The ice bath is removedand the mixture stirred at room temperature for 2 hours. The solution isrechilled to 0° C. and a solution of 2-bromo-1-phenyl-hexan-1-one (2-1)(16.8 g, 66 mmol) in DMSO (50 mL) is added slowly. The ice bath isremoved and the mixture stirred overnight. Water (500 mL) is added andthe mixture is extracted with EtOAc (4×150 mL). The combined extractsare washed with brine (300 mL), dried (Na₂SO₄), and evaporated, toprovide the product as a light yellow oil. LC-MS (M+1) 307. ¹H NMR (δ,CDCl₃) 7.98-8.02 (m, 2H), 7.46-7.60 (m,3H), 4.18-4.28 (m, 1H), 4.03-4.12(m, 1H), 3.80 (s, 3H), 3.6.1 (s, 3H), 1.55-1.63 (m, 2H), 1.02-1.20 (m,4H), 0.76 (t, J=0.72 Hz, 3H).

3-Benzoyl-heptanoic acid methyl ester. Water (3 ml, 166 mmol) and NaCl(5.3 g, 90.2 mmol) are added to a solution of2-(1-benzoyl-pentyl)-malonic acid dimethyl ester (25.0 g, 81.7 mmol) inDMSO (150 mL). The mixture is heated at 150° C. for 6 hours. Water (450mL) is added and the mixture is extracted with EtOAc (4×150 mL). Thecombined extracts are washed with brine (300 mL), dried (Na₂,SO₄), andevaporated, to provides 3-Benzoyl-heptanoic acid methyl ester as a lightyellow oil. LC-MS (M+1) 249. This compound without further purificationis used directly to the next step.

5-Butyl-6-phenyl-4,5-dihydro-2H-pyridazin-3-one. A solution of3-benzoyl-heptanoic acid methyl ester (4.72 g, 19 mmol) and hydrazinemonohydrate (4.6 ml, 95 mmol) in ethanol (50 mL) is reflux for 12 hours.The solvent and excess hydrazine monohydrate is removed in vacuo and theresidue is partitioned with EtOAc (80 mL) and water (80 mL). The layersare separated and the organic phase is washed with brine (60 mL), dried(Na₂SO₄) and evaporated in vacuo. Hash column chromatography of theresidue (silica gel, 2:1 hexane, EtOAc) provides a creamy solid. LC-MS(M+1) 231. ¹H NMR (δ, CDCl₃) 8.84 (s, 1H), 7.72-7.79 (m, 2H), 7.37-7.43(m, 3H), 3.19-3.30 (m, 1H), 2.62 (d, J=6.8 Hz, 2H), 1.52-1.62 (m, 2H),1.21-1.43 (m, 4H), 0.87 (t, J=7.8 Hz, 3H).

5-Butyl-6-phenyl-2H-pyridazin-3-one. A solution of bromine (0.94 ml,18.2 mmol) in HOAc (10 mL) is added dropwise to a solution of5-butyl-6-phenyl-4,5-dihydro-2H-pyridazin-3-one (3-8g, 16.5 mmol) inHOAc (40 mL) at 80° C. After the addition is complete, the heating iscontinued for 30 minutes and the solvent is evaporated in vacuo. Theresidue is partitioned between saturated aqueous NaHCO₃ solution (50 mL)and EtOAc (50 mL) and the organic layer washed with water (35 mL), brine(35 mL), and then dried (Na₂SO₄). Evaporation of the solvent in vacuoprovides the desired product as a yellow solid. LC-MS (M+1) 229. ¹H NMR(δ, CDCl₃) 12.39 (s, 1H), 7.39-7.48 (m, 5H), 6.83 (s, 1H), 2.41 (t,J=7.2 Hz, 2H), 1.20-1.43 (m, 4H), 0.77 (t, J=7.7 Hz, 3H).

5-Butyl-3-chloro-6-phenyl-pyridazine.5-butyl-6-phenyl-2H-pyridazin-3-one (3.6 g, 15.8 mmol)) is dissolved inPOCl₃ (40 mL) and the solution is heated at 85° C. for 3 hours. Theexcess POCl₃ is evaporated in vacuo and the residue is partitionedbetween saturated aqueous NaHCO₃ solution (50 mL) and EtOAc (50 mL). Theorganic layer is washed with water (35 mL), brine (35 mL), and thendried (Na₂SO₄). Evaporation of the solvent in vacuo provides a yellowoil. Flash column chromatograph (silica gel, 4:1 hexane, EtOAc) providesa light yellow oil. LC-MS (M+1) 247. ¹H NMR (δ, CDCl₃) 7.47 (s, 5H),7.42 (s, 1H), 2.62 (t, J=7.2 Hz, 2H), 1.43-1.53 (m, 2H), 1.18-1.31 (m,2H), 0.81 (t, J=7.5 Hz, 3H).

5-Butyl-3-chloro-4-hydroxymethyl-6-phenyl-pyridazine. Concentrated H₂SO₄(0.17 ml, 3.2 mmol), (NH₄)₂S₂O₈ (0.575 g, 2.52 mmol) and AgNO₃ (4 mg)are added to a solution of 4-butyl-6-chloro-3-phenyl-pyridazine (0.526g, 2.1 mmol) in MeOH (12 mL) and water (6 mL). The mixture is heated at75° C. for 3 h and the solvent is then evaporated in vacuo. The residueis partitioned between saturated aqueous NaHCO₃ solution (30 mL) andEtOAc (30 mL) and the organic layer is washed with water (25 mL), brine(25 mL), and then dried (Na₂SO₄). Evaporation of the solvent in vacuoprovides a yellow oil. Flash column chromatography (silica gel, 2:1hexane, EtOAc) provides the product as a light yellow solid. LC-MS (M+1)277. ¹H NMR (δ, CDCl₃) 7.42-7.50 (m, 5H), 4.87 (s, 2H), 2.75 (t, J=8.1Hz, 2H), 2.40 (s, 1H), 1.34-1.43 (m, 2H), 1.17-1.25 (m, 2H), 0.74 (t,J=7.5 Hz, 3H).

5-Butyl-3-chloro-4-chloromethyl-6-phenyl-pyridazine hydrochloride. To asolution of 4-butyl-6-chloro-5-hydroxymethyl-3-phenyl-pyridazine (0.32g, 1.16 mmol) in CH₂Cl₂ (5 mL) is added SOCl₂ (2 mL). The resultingclear solution is stirred at room temperature for 3 hours. The solventis removed in vacuo and the residue is dissolved in toluene (5 mL) andevaporated to remove the remaining SOCl₂. The resulting semi-solid isused directly for the next step. LC-MS (M+1) 295.

Benzo[1,3]dioxol-5-ylmethyl-(5-butyl-3-chloro-6-phenyl-pyridazin-4-ylmethyl)-amine.Piperonylamine (0.37 ml, 3 mmol) and K₂CO₃ (0.69 g, 3 mmol) are added toa solution of 5-butyl-3-chloro-4-chloromethyl-6-phenyl-pyridazinehydrochloride (0.176 g, 0.6 mmol) in CH₃CN (12 mL). The mixture isstirred at room temperature overnight. The solvent is removed in vacuoand the residue is partitioned between water (20 mL) and EtOAc (20 mL).The organic layer is washed with water (15 mL), brine (15 mL), and thendried (Na₂SO₄). Evaporation of the solvent in vacuo provides a yellowoil. Flash column chromatography (silica gel, 10:0.5:0.05 CH₂Cl₂, MeOH,NH₄OH) of the residue provides a light yellow oil. LC-MS (M+1) 410. ¹HNMR (δ, CDCl₃) 7.41-7.49 (m, 5H), 6.87 (s, 1H), 6.74-6.82 (m, 2H), 5.94(s, 2H), 3.87 (s, 2H), 3.81 (s, 2H), 2.59 (t, J=7.8 Hz, 2H), 1.81 (s,1H), 1.25-1.35 (m, 2H), 1.07-1.17 (m, 2H), 0.70 (t, J=7.2 Hz, 3H).

Benzo[1,3]dioxol-5-ylmethyl-butyl-(5-butyl-3-chloro-6-phenyl-pyridazin-4-ylmethyl)-amine.PrCHO (0.036 ml, 0.4 mmol) is added to a solution ofbenzo[1,3]dioxol-5-ylmethyl-(5butyl-3-chloro-6-phenyl-pyridazin-4-ylmethyl)-amine(0.04 g, 0.1 mmol) in CH₂ClCH₂Cl (5 mL) and HOAc (0.5 mL). The mixtureis stirred at room temperature for 45 min, NaBH(OAc)₃ (0.127 g, 0.6mmol) is then added and the mixture is stirred overnight. The solvent isremoved in vacuo, the residue is partitioned between saturated aqueousNaHCO₃ solution (20 mL) and EtOAc (20 mL), the organic layer is washedwith water (15 mL), brine (15 mL), and then dried (Na₂SO₄). Evaporationof the solvent in vacuo provides a yellow oil. Preparative TLC(10:0.5:0.05 CH₂Cl₂, MeOH, NH₄OH) provides the purified product as alight yellow oil. LC-MS (M+1) 466. ¹H NMR (δ, CDCl₃) 7.39-7.47 (m, 5H),6.77 (s, 1H), 6.70 (s, 2H), 5.90 (s, 2H), 3.76 (s, 2H), 3.49 (s, 2H),2.75 (t, J=7.2 Hz, 2H), 2.45 (t, J=7.2 Hz, 2H), 1.45-1.54 (m, 2H),0.92-1.32 (m, 6H), 0.82 (t, J=7.2 Hz, 3H), 0.63 (t, J=7.2 Hz, 3H).

Example 16 Preparation ofBis-benzo[1,3]dioxol-5-ylmethyl-(5-butyl-3-chloro-6-phenyl-pyridazin-4-ylmethyl)-amine(181)

Piperonyl (0.06 g, 04 mmol), is added to a solution ofbenzo[1,3]dioxol-5-ylmethyl-(5-butyl-3-chloro-6-phenyl-pyridazin-4-ylmethyl)-amine(0.042 g, 0.1 mmol) in CH₂ClCH₂Cl (5 mL) and HOAc (0.5 mL). The mixtureis stirred at room temperature for 45 minutes, NaBH(OAc)₃ (0.127 g, 0.6mmol) is then added and the mixture is stirred overnight. The solvent isremoved in vacuo, the residue is partitioned between saturated aqueousNa₄₄CO₃ solution (20 mL) and EtOAc (20 mL), and the organic layer iswashed with water (15 mL), brine (15 mL), and then dried (Na₂SO₄).Evaporation of the solvent a in vacuo provides the compound shown aboveas a yellow oil. Preparative TLC (3:1 Hexane, EtOAc) of the residueprovides a light yellow oil. LC-MS (M+1) 544, ¹H NMR (δ, CDCl₃)7.37-7.48 (m, 5H), 6.77 (s, 2H), 6.72 (s, 4H), 5.91 (s, 4H), 3.78 (s,2H), 3.49 (s, 4H), 2.69 (t, J=7.2 Hz, 2H), 0.85-1.02 (m, 4H), 0.59 (t,J=7.0 Hz, 3H).

Example 17 Preparation ofBenzo[1,3]dioxol-5-ylmethyl-(5-butyl-3-chloro-6-phenyl-pyridazin-4-ylmethyl)-(3-ethoxy-benzyl)-amine(182)

3-Ethoxybenzaldehyde (0.062 ml, 0.44 mmol) is added to a solution ofbenzo[1,3]dioxol-5-ylmethyl(5-butyl-3-chloro-6-phenyl-pyridazin-4-ylmethyl)-amine) (0.045 g, 0.1mmol) in CH₂ClCH₂Cl (5 mL) and HOAc (0.5 mL). The mixture is stirred atroom temperature for 45 minutes, NaBH(OAc)₃ (0.140 g, 0.66 mmol) is thenadded and the mixture is stirred over night. The solvent is removed invacuo, the residue is partitioned between saturated aqueous NaHCO₃solution (20 mL) and EtOAc (20 mL), the organic layer is washed withwater (15 mL), brine (15 mL), and then dried (Na₂SO₄). Evaporation ofthe solvent in vacuo provides the product shown above as a yellow oil.Preparative TLC (3:1 Hexane, EtOAc) of the residue provides purifiedproduct as a light yellow oil. LC-MS (M+1) 544. ¹H NMR (δ, CDCl₃)7.36-7.48 (m, 5H), 7.18 (t, J=7.2 Hz, 1H), 6.70-6.87 (m, 6H), 5.91 (s,2H), 4.00 (q, J=7.0 Hz, 2H), 3.80 (s, 2H), 3.56 (s, 2H), 3.52 (s, 2H),2.70 (t, J=7.5 Hz, 2H), 1.41 (t, J=7.2 Hz, 2H), 0.84-1.02 (m, 4H), 0.58(t, J=7.2 Hz, 3H).

Example 18 Preparation of(5-butyl-3-chloro-6-phenyl-pyridazin-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-(3-ethoxy-benzyl)-amine(183)

(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-(3-ethoxy-benzyl)-amine (0.211g, 0.7 mmol) and K₂CO₃ (0.69 g, 3 mmol) is added to a solution of5-butyl-3-chloro-4-chloromethyl-6-phenyl-pyridazine hydrochloride (0.175g, 0.6 mmol) in CH₃CN (15 mL). The mixture is stirred at 80° C.overnight. The solvent is removed in vacuo and the residue ispartitioned between water (20 mL) and EtOAc (20 mL). The organic layeris washed with water (15 mL), brine (15 mL), then dried (Na₂SO₄).Evaporation of the solvent in vacuo provides a yellow oil. PreparativeTLC (3:1 Hexane, EtOAc) of the residue provides a light yellow oil.LC-MS (M+1) 558 ¹H NMR (δ, CDCl₃) 7.36-7.48 (m, 5H), 7.18 (t, J=7.2 Hz,1H), 6.72-6.89 (m, 6H), 4.21 (s, 4H), 4.01 (q, J=7.2 Hz, 2H), 3.80 (s,2H), 3.56 (s, 2H), 3.50 (s, 2H), 2.70 (t, J=7.2 Hz, 2H), 1.41 (t, J=6.9Hz, 3H), 0.84-1.02 (m, 4H), 0.58 (t, J=7.2 Hz, 3H).

Example 19 Preparation ofBis-benzo[1,3]dioxol-5-ylmethyl-[2-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-ethyl]-amine(191)

(3 butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetonitrile(187). Triethylamine(1.0 ml, 7.18 mmol) and methanesulfonyl chloride (0.37 ml, 4.89 mmol)are added to a stirred solution of(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-methanol (1.0 g, 3.26 mmol)(185)in anhydrous acetonitrile (30 mL) at 0° C. After proceeding for 1 hourthe reaction is concentrated at 60° C. to remove all solvent and excessMsCl. Cold acetonitrile is added to precipitate triethylammoniumchloride, which is then removed by filtration. The remaining solution ofmesylate product is reduced to a 30 ml volume, tetraethylammoniumcyanide (1.53 g, 9.79 mmol) is added to the solution, and the reactionis heated at 60° C. overnight. Solvent is removed in vacuo and the crudeproduct dissolved in ethyl acetate (100 mL). The organic layer is washedwith saturated sodium bicarbonate (2×100 mL), brine (1×100 mL) and driedover magnesium sulfate. The sample is filtered, concentrated andpurified by flash chromatography on SiO₂ using an eluent of 2:3acetate:hexane to afford(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetonitrile(187) as a lightorange oil.

(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetic acid methyl ester(188).Hydrogen chloride gas is bubbled into solution of(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetonitrile (187) (640 mg, 2.03mmol) in methanol (30 mL) at 0° C. for 10 minutes, followed by stirringfor 30 minutes. Water (0.0365 ml, 2.03 mmol) is then added and thereaction refluxed at 80° C. for 2 hours. The methanol is then removed invacuo, the reaction crude is dissolved in ethyl acetate (100 mL), andthe organic layer is washed with saturated sodium bicarbonate (1×100mL), brine (1×100 mL), and dried over magnesium sulfate. The sample isfiltered, concentrated and purified by flash chromatography on SiO₂using an eluent of 2:3 ethyl acetate:hexane to afford(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetic acid methyl ester (188)as a colorless oil.

(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetic acid (189) 5N sodiumhydroxide (100 mL) is added to a solution of(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetic acid methyl ester (188)(460 mg, 1.32 mmol) in ethanol (100 mL). The mixture is stirred at 85°C. for 4 hours. All ethanol is removed in vacuo and the crude extractedwith ethyl ether (2×50 mL). The aqueous fraction is then acidified to pH2 using 1M HCl and the product extracted into ethyl acetate (100 mL).The organic fraction is washed with water (1×100 mL), brine (1×100 mL),and dried over magnesium sulfate. Concentration in vacuo affords(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetic acid (189) as a whitefoam.

N,N-bis-benzo[1,3]dioxol-5-ylmethyl-2-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetamide(190). Triethyl amine (0.23 ml, 1.64 mmol) andbenzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate(330 mg, 0.748 mmol) are added to a solution of(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetic acid (250 mg, 0.748 mmol)(189) in N,N-dimethylformamide (15 mL) and the reaction mixture isallowed to stir overnight at room temperature. The reaction is dilutedwith ethyl ether (100 mL) and the organic layer washed with saturatedsodium bicarbonate (3×100 mL), brine (1×100 mL), and is dried overmagnesium sulfate. The crude is filtered, concentrated in vacuo, andflash chromatographed on SiO₂ using an eluent of 1:1 ethyl ether:hexaneto affordN,N-bis-benzo[1,3]dioxol-5-ylmethyl-2-(3-butyl-2,5-diphenyl-3-imidazol-4-yl)-acetamide(190) as a colorless waxy solid.

Bis-benzo[1,3]dioxol-5-ylmethyl-[2-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-ethyl]-amine(191). A solution ofN,N-bis-benzo[1,3]dioxol-5-ylmethyl-2-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetamide(150 mg, 0.249 mmol) in tetrahydrofuran (25 mL) is cooled to 0° C. undera nitrogen atmosphere. Lithium aluminum hydride (95%, 30 mg, 0.747 mmol)is added in one portion and the reaction allowed to stir overnightwarming to room temperature. Water (0.03 mL), sodium hydroxide (15%solution, 0.03 mL), and water (0.09 mL) are added and the reactionmixture is allowed to stir at 0° C. for 15 minutes. Magnesium sulfate isthen added and the crude solution is filtered through a bed of Celitewashing with 2% methanol in dichloromethane (100 mL). The crude sampleis concentrated in vacuo and flash chromatographed on SiO₂ using aneluent of dichloromethane:methanol 95:5 to affordbis-benzo[1,3]dioxol-5-ylmethyl-[2-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-ethyl]-amineas a colorless syrup.

Example 20 Preparation of(5-Butyl-6-phenyl-pyrimidin-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-(3-ethoxy-benzyl)-amine

Step 1. Preparation of 2-Butyl-3-dimethylamino-1-phenyl-propenone

A solution of hexanophenone (1.76 g, 100.0 mmol) in dimethylformamidedimethyl acetal (DMF-DMA) (7.07 ml, 50.0 mmol) is stirred at 150° C. ina sealed tube for 16 hours. After cooling, the solution is concentratedin vacuo. EtOH is added and then removed in vacuo in order to aid in theremoval of DMF and DMF-DMA. 2-Butyl-3-dimethylamino-1-phenyl-propenoneis obtained as an orange oil and is used directly in the next reaction.¹H NMR (CDCl₃, 300 MHz) δ 7.42-7.39 (m, 2H), 7.36-7.32 (m, 3H), 6.80 (s,1H), 3.01 (s, 6H), 2.61-2.56 (m, 2H), 1.48-1.36 (m, 4H), 0.93 (t, J=7.2Hz, 3H) ppm.

Step 2. Preparation of 5-butyl-4-phenyl-pyrimidine

Crude 2-butyl-3-dimethylamino-1-phenyl-propenone is dissolved in EtOH(˜5-6 mL) and treated with formamidine acetate (3.12 g, 30.0 mmol). Thereaction mixture is then stirred at 120° C. in a sealed tube for 6hours. After cooling, the reaction mixture is partitioned between EtOAcand H₂O (50 mL). The layers are separated, and the organic layer iswashed with additional H₂O (50 mL) and brine (50 mL). The aqueous washesare reextracted once with EtOAc, and the combined extracts are driedover Na₂SO₄ and concentrated. The residue is purified by flashchromatography on silica gel. Elution with 3:1 EtOAc-hexanes affordspure 5-butyl-4-phenyl-pyrimidine as a light yellow oil. ¹H NMR (CDCl₃,300 MT-1z) δ 9.11 (s, 1H), 8.64 (s, 1H), 7.55-7.46 (m, 5H), 2.73-2.68(m, 2H), 1.56-1.45 (m, 2H), 1.27 (sext, J=7.2 Hz, 2H), 0.83 (t, J=7.2Hz, 3H) ppm. MS: m/z 213 [M+1].

Step 3. Preparation of 5-butyl-4-methyl-6-phenyl-pyrimidine

1.4 M MeLi in Et₂O (1.54 ml, 2.16 mmol) is slowly added to a solution of5-butyl-4-phenyl-pyrimidine (436 mg, 2.05 mmol) in Et₂O (6 mL) at −30°C. under N₂. The reaction mixture is stirred at −30° C. for 30 minutesand then at 0° C. for 45 minutes. Next, a solution of AcOH (0.12 mL) andH₂O (0.02 mL) in THF (2 mL) is added, followed by a solution of2,3-dichloro-5,6-dicyano-1,4-benzophenone (DDQ) (466 mg, 2.05 mmol) inTHF (5 mL). The resulting mixture is stirred at room temperature for 5minutes, recooled to 0° C., and then treated with 3.0 M aqueous NaOH.The mixture is stirred at 0° C. for 5 minutes, diluted with H₂O, andextracted twice with Et₂O. The combined extracts are dried over Na₂SO₄and concentrated. The dark residue is purified by flash chromatographyon silica gel. Elution with 2:1 Hex-EtOAc followed by 1:1 hexanes-EtOAcaffords 5-butyl-4-methyl-6-phenyl-pyrimidine as a light yellow oil. ¹HNMR (CDCl₃, 300 MHz) δ 8.95 (s, 1H), 7.45 (m, 5H), 2.67-2.62 (m, 2H),2.61 (s, 3H), 1.48-1.40 (m, 2H), 1.25 (sext, J=7.2 Hz), 0.82 (t, J=7.2Hz, 3H) ppm. MS: m/z 227 [M+1].

Step 4. Preparation of 4-bromomethyl-5-butyl-6-phenyl-pyrimidine

A solution of 5-butyl-4-methyl-6-phenyl-pyrimidine (320 mg, 1.14 mmol)and Br₂ (0.08 ml, 1.48 mmol) in AcOH (2 mL) is stirred at 80° C. for 2hours. After cooling, the solution is concentrated. The residue is thenpartitioned between Et₂O and half saturated aqueous NaHCO₃. The layersare separated, and the aqueous layer is reextracted once with Et₂O. Thecombined extracts are dried over Na₂SO₄ and concentrated. The residue ispurified by flash chromatography on silica gel. Elution with 3:1hexanes-EtOAc affords 4-bromomethyl-5-butyl-6-phenyl-pyrimidine and asmall amount of an unidentified impurity. ¹H NMR (CDCl₃, 300 MHz) δ 9.08(s, 1H), 7.47 (s, 5H), 4.57 (s, 2H), 2.79-2.74 (m, 2H), 1.52-1.42 (m,2H), 1.38-1.20 (m, 2H), 0.80 (t, J=7.41Hz, 3H) ppm.

Step 5. Preparation of(5-butyl-6-phenyl-pyrimidin-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-(3-ethoxy-benzyl)-amine

A mixture of 4-bromomethyl-5-butyl-6-phenyl-pyrimidine (86 mg),(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-(3-ethoxy-benzyl)-amine (93mg, 0.310 mmol), and K₂CO₃ (195 mg, 1.4 mmol) in CH₃CN (2.0 mL) isstirred at reflux for 1 h and at room temperature for 16 hours. Thereaction mixture is then diluted with CH₂Cl₂ and filtered. The filtrateis concentrated, and the residue purified by preparative TLC, developingwith 2:1 hexanes-EtOAc (+0.5% Et₃N). The band containing product affordspure (5-butyl-6-phenylpyrimidin-4-ylmethyl)-(9,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-(3-ethoxy-benzyl)-amine¹H NMR (CDCl₃, 300 MHz) δ 8.98 (s, 1H), 7.42 (r, 5H), 7.19 (t, J=8.0 Hz,1H), 6.92-6.73 (m, 6H), 4.22 (s, 4H), 4.01 (q, J=6.9 Hz, 2H), 3.76 (s,2H), 3.60 (s, 2H), 3.54 (s, 2H), 2.70-2.64 (m, 2H), 1.41 (t, J=6.9 Hz,3H), 1.09-0.99 (m, 2H), 0.91 (sext, J=7.9 Hz, 2H), 0.61 (t, J=7.2 Hz,3H) ppm. MS: m/z 524 [M+1].

Example 21 Preparation of4-{[(5-Butyl-2-isobutoxy-6-phenyl-pyrimidin-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-methyl}-benzoicacid

Step 1. Preparation of5-butyl-6-methyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

Sodium metal (1.85 g, 80.5 mmol) is dissolved in EtOH (50 mL). Next,thiourea (5.11 g, 67.1 mmol) is added to the NaOEt solution, followed byethyl 2-n-butylacetoacetate (2.5 g, 13.4 mmol). The reaction mixture isstirred at reflux for 3 hours and then allowed to cool to roomtemperature overnight. The EtOH is removed in vacuo. The residue is thensuspended in H₂O (50 mL) and the resulting mixture carefully treatedwith concentrated HCl (−7.5 mL) just until pH 4 is reached. Afterstirring for 15 minutes, the suspension is filtered, and the solidthoroughly washed with H₂O. Drying affords pure5-butyl-6-methyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one as a slightlyoff-white solid. ¹H NMR (DMSO-d₆, 300 MHz) δ 12.28 (br s, 1H), 12.05 (brs, 1H), 2.21 (m, 2H), 2.18 (s, 3H), 1.30-1.21 (m, 4H), 0.85 (t, J=6.9Hz, 3H) ppm. MS; m/z 199 [M+1].

Step 2. Preparation of 5-butyl-6-methyl-1H-pyrimidine-2,4-dione

A suspension of 5-butyl-6-methyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-onein 10% aqueous chloroacetic acid (100 mL) is stirred at reflux for 3hours and then allowed to cool to room temperature. The suspension iscooled in an ice bath for a few minutes and then filtered. The solid isthoroughly washed with H₂O and dried, yielding pure5-butyl-6-methyl-1H-pyrimidine-2,4-dione as a white solid. ¹H NMR(DMSO-d₆, 300 MHz) δ 10.86 (br s, 1H), 10.57 (br s, 1H), 2.17 (m, 2H),2.01 (s, 3H), 1.25 (m, 4H), 0.85 (t, J=6.9 Hz, 3H) ppm. MS: m/z 183[M+1].

Step 3. Preparation of 5-Butyl-2,4-dichloro-6-methyl-pyrimidine

A mixture of 5butyl-6-methyl-1H-pyrimidine-2,4-dione (1.76 g, 9.66 mmol)in POCl₃ (15 mL), containing DMF (0.065 mL) is stirred at reflux for 4hours. After cooling, the yellow solution is concentrated in vacuo. Theflask is placed in an ice bath, and crushed ice (˜50-100g) is added tothe residue. The mixture is stirred vigorously until the ice melts. Themixture is then extracted with EtOAc. The extract is washed with H₂O (50mL) and brine (50 mL), dried over Na₂SO₄, and concentrated to providepure 5-butyl-2,4-dichloro-6-methyl-pyridine as a yellow oil. ¹H NMR(CDCl₃, 300 MHz) δ 2.74-2.57 (m, 2H), 2.56 (s, 3H), 1.55-1.40 (m, 4H),0.97 (t, J=7.1 Hz, 3H) ppm. MS: m/z 219 [M+1].

Step 4. Preparation of 5-Butyl-2-chloro-4-methyl-6-phenyl-pyrimidine

A mixture of 5-butyl-2,4-dichloro-6-methyl-pyrimidine (711 mg, 3.24mmol), phenylboronic acid (475 mg, 3.89 mmol), Na₂CO₃ (1.03 g, 9.73mmol), and Pd(PPh₃)₄ (187 ma, 0.162 mmol) in toluene-EtOH—H₂ (4 ml-0.5ml-2 mL) is stirred at reflux for 6 hours. After cooling, the reactionmixture is diluted with H₂O and extracted with EtOAc. The extract isthen washed with brine, dried over Na₂SO₄, and concentrated. The residueis purified by flash chromatography on silica gel. Elution with 8:1hexanes-EtOAc followed by 7:1 hexanes-EtOAc affords5-butyl-2-chloro-4-methyl-6-phenyl-pyrimidine as a colorless oil. ¹H NMR(CDCl₃, 300 MHz) δ 7.45 (m, 5H), 2.65-2.62 (m, 2H), 2.60 (s, 3H),1.46-1.36 (m, 2H), 1.25 (sext, J=7.2 Hz, 2H), 0.81 (t, J=7.2 Hz, 3H)ppm.

Step 5. Preparation of4-Bromomethyl-5-butyl-2-chloro-6-phenyl-pyrimidine

A solution of the 5butyl-2-chloro-4-methyl-6-phenyl-pyrimidine (215 mg,0.825 mmol) and Br₂ (0.042 ml, 0.825 mmol) in AcOH (2 mL) is stirred at80° C. for 21 hours. After cooling, the solution is concentrated. Theresidue is partitioned between Et₂O and half saturated aqueous NaHCO₃.The layers are separated, and the aqueous layer is reextracted once withEt₂O. The combined extracts are dried over Na₂SO₄ and concentrated to305 mg of crude 4-bromomethyl-5-butyl-2-chloro-6-phenyl-pyrimidine,which also contains small amounts of SM and dibromo material. Thismaterial is used without further purification.

Step 6. Preparation of4-{[(5-butyl-2-chloro-6-phenyl-pyrimidin-1-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-methyl}-benzoicacid methyl ester

A solution of impure 4-bromomethyl-5-butyl-2-chloro-6-phenyl-pyrimidine(288 mg) and4-{[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-methyl}-benzoicacid methyl ester (190 mg, 0.606 mmol) in CH₃CN containing K₂CO₃ (300mg) is stirred at room temperature. The reaction is monitored by TLCuntil complete consumption of4-bromomethyl-5-butyl-2-chloro-6-phenyl-pyrimidine (24 hours). Themixture is then diluted with CH₂Cl₂ and filtered. The filtrate isconcentrated, and the resulting residue is purified by flashchromatography on silica gel. Elution with 5:1 hexanes-EtOAc followed by4:1 hexanes-EtOAc affords 215 mg of pure 4-{[(5-butyl-2-chloro-6-phenylpyrimidin-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-methyl}-benzoicacid methyl ester ¹H NMR (CDCl₃, 300 MHz) δ 7.97 (d, J=8.1 Hz, 2H),7.44-7.33 (m, 7H), 6.84 (s, 1H), 6.79 (s, 2H), 4.22 (s, 4H), 3.90 (s,3H), 3.74 (s, 2H), 3.72 (s, 2H), 3.55 (s, 2H), 2.64-2.56 (m, 2H), 1.01(m, 2H), 0.90 (sext, J=7.2 Hz, 2H), 0.61 (t, J=7.2 Hz, 3H) ppm. MS: m/z572 [M+1].

Step 7. Preparation of4-{[(5-butyl-2-isobutoxy-6-phenyl-pyrimidin-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-methyl}-benzoicacid

NaH (60% dispersion in mineral oil) (˜40 mg) is added to a solution of4-{[(5-butyl-2-chloro-6-phenyl-pyrimidin-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-methyl}-benzoicacid methyl ester (46 mg, 0.0804 mmol) in THF (3 mL) containing isobutylalcohol (0.5 mL) at room temperature. The mixture is stirred at roomtemperature for 5 minutes and then at reflux for 2 hours. Next, H₂O (0.5mL) is added and heating is continued for an additional 30 minutes.After cooling to room temperature, the reaction mixture is treated witha few drops of AcOH until pH 4-5. The mixture is then diluted with H₂Oand extracted twice with CH₂Cl₂. The combined extracts are dried overNa₂SO₄ and concentrated. The residue is purified by preparative TLC,eluting with 20:1 CHCl₃—MeOH. The band containing the product affords28.4 mg4-{[(5-butyl-2-isobutoxy-6-phenyl-pyrimidin-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-methyl}-benzoicacid as a colorless gum. ¹H NMR (CDCl₃, 300 MHz) δ 8.02 (br, 2H), 7.39(br, 7H), 6.87 (br s, 1H), 6.78 (br s, 2H), 4.21 (br s, 4H), 4.12 (br d,J=6.3 Hz, 2H), 3.70 (br, 4H), 3.54 (br s, 2H), 2.54 (br m, 2H), 2.13(br, 1H), 1.02 (d, J=6.3 Hz, 6H), 0.94 (br 4H), 0.60 (br, 3H) ppm. MS:m/z 596 [M+1].

Example 22 Preparation of5-{3-[(3-Butyl-5-chloro-2-phenyl-3H-imidazol-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-propyl}-isoxazol-3-oland5-{3-[(3-butyl-5-chloro-2-phenyl-3H-imidazol-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-pentyl}-isoxazol-3-ol

Step 1. Preparation of 5-(3-benzyloxy-isoxazol-5-yl)-propenal (major)and 5-(3-benzyloxy-isoxazol-5-yl)-penta-2,4-dienal

(Triphenylphosphoranylidene)acetaldehyde (785 mg, 2.58 mmol) is added inone portion to a solution of 3-benzyloxy-isoxazole-5-carbaldehyde (403mg, 1.98 mmol) (prepared according to Eur. J. Org. Chem. 1998, 473-479)in 5:1 toluene-CH₃CN (12 mL) at room temperature. The reaction mixtureis stirred at room temperature overnight. The dark solution is thenconcentrated in vacuo, and the residue purified by flash chromatographyon silica gel. Elution with 4:1 hexanes-EtOAc affords an approximately2:1 mixture of 3-(3-benzyloxy-isoxazol-5-yl)-propenal (major) and5-(3-benzyloxy-isoxazol-5-yl)penta-2,4-dienal (minor). Diagnostic ¹H NMRsignals: Major; ¹H NMR (CDCl₃, 300 MHz) δ 9.72 (d, J=7.8 Hz, 1H), 6.24(s, 1H), 5.31 (s, 2H) ppm. Minor: ¹H NMR (CDCl₃, 300 MHz) δ 9.66 (d,J=7.8 Hz, 1H), 6.04 (s, 1H), 5.30 (s, 2H) ppm.

A solution of the enal mixture in 10 ml of EtOAc containing a catalyticamount of 10% Pd/C is stirred under an atmosphere of H₂ (double-stuffedballoon) for 6 hours. The reaction mixture is then filtered through apad of Celite. The filtrate is concentrated to a colorless oil, which isused without further purification.

Step 2. Preparation of[3-(3-benzyloxy-isoxazol-5-yl)-propyl]-(3-butyl-5-chloro-2-phenyl-3H-imidazol-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amine(major) and[5-(3-benzyloxy-isoxazol-5-yl)-pentyl]-(3-butyl-5-chloro-2-phenyl-3H-imidazol-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amine(minor)

5 drops of AcOH is added to a solution of(3-butyl-5-chloro-2-phenyl-3H-imidazol-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amine(134 mg, 0.325=mmol) and the crude aldehyde mixture from the previousreaction (75 mg) in 1,2-dichloroethane (5 mL). The mixture is stirred atrt for 15 min., and then NaBH(OAc)₃ (103 mg, 0.488 mmol) is added in oneportion. The reaction mixture is stirred at room temperature for 60hours. Next, half saturated NaHCO₃ is added. The resulting mixture isstirred for 15 minutes, and then extracted two times with CH₂Cl₂. Thecombined extracts are dried over Na₂SO₄ and concentrated. The residue ispurified by preparative TLC, to afford an inseparable mixture of[3-(3-benzyloxy-isoxazol-5-yl)-propyl]-(3-butyl-5-chloro-2-phenyl-3H-imidazol-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amine(major) and[5-(3-benzyloxy-isoxazol-5-yl)-pentyl]-(3-butyl-5-chloro-2-phenyl-3H-imidazol-4-ylmethyl)(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amine(minor). Diagnostic ¹H NMR signals: Major: ¹H NMR (CDCl₃, 300 MHz) δ5.52 (s, 1H), 5.21 (s, 2H) ppm. Minor: ¹H NMR (CDCl₃, 300 MHz) δ 5.61(s, 1H), 5.23 (s, 2H) ppm. MS: m/z 627 [M+1] (major) and 655 [M+1](minor).

Step 3. Preparation of5-{3-[(3-Butyl-5-chloro-2-phenyl-3H-imidazol-4-ylmethyl)-(23-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-propyl}-isoxazol-3-ol and5-{3-[(3-Butyl-5-chloro-2-phenyl-3H-imidazol-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-pentyl}-isoxazol-3-ol

A solution of the amine mixture from the previous reaction in 30% HBr inAcOH (5 mL) is stirred at room temperature overnight. The solution isconcentrated in vacuo, and the residue is purified by reversed phaseHPLC in order to separate the two amines. The pure fractions areconcentrated to approximately 10% of their original volume. Theremaining mixtures are treated with a few drops of AcOH in order toadjust the pH to approximately 4. The mixtures are then extracted threetimes with CH₂Cl₂. The combined extracts are dried over Na₂SO₄ andconcentrated to the pure amines as colorless gums.

5-{3-[(3-Butyl-5-chloro-2-phenyl-3H-imidazol-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-propyl}-isoxazol-3-ol.¹H NMR (CDCl₃, 300 MHz) δ 7.52-7.49 (m, 2H), 7.44-7.40 (m, 3H),6.81-6.73 (m, 3H), 5.50 (s, 1H), 4.22 (s, 4H), 3.95 (m, 2H), 3.52 (s,2H), 3.46 (s, 2H), 2.58 (t, J=7.7 Hz, 2H), 2.51 (t, J=6.8 Hz, 2H), 1.83(pent, J=7.2 Hz, 2H), 1.40-1.28 (m, 2H), 1.99 (sext, J=7.2 Hz, 2H), 0.71(t, J=7.2 Hz, 3H) ppm. MS: m/z 537 [M+1].

5-{5-[(3-Butyl-5-chloro-2-phenyl-3H-imidazol-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-pentyl}-isoxazol-3-ol:¹H NMR (CDCl₃, 300 MHz) δ 7.52-7.49 (m, 2H), 7.44-7.39 (m, 3H),6.81-6.72 (m, 3H), 5.60 (s, 1H), 4.21 (s, 4H), 3.97 (m, 2H), 3.51 (s,2H), 3.44 (s, 2H), 2.57 (t, J=7.4 Hz, 2H), 2.44 (t, J=7.2 Hz, 2H),1.61-1.25 (m, 8H), 1.02 (sext, J=7.2 Hz, 2H), 0.73 (t, J=7.2 Hz, 3H)ppm. MS: m/z 565 [M+1].

Example 23 Preparation ofBis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-5-phenyl-2-O-tolyl-3H-imidazol-4-ylmethyl)-amine

To the suspension of sodium hydride (2.40 g, 60% mineral oil suspension,60 mmol) in 30 ml of anhydrous DMF is added a solution of4-phenylimidazole (7.21 g, 50 mmol) in 30 ml of DMF at room temperature,the resulting mixture is stirred at 70° C. 1h, and then cooled to roomtemperature followed by the dropwise addition of iodobutane (9.66 g 52.5mmol, 1.05 eq.). The mixture is stirred at room temperature for 1 h,heated to 70° C. and stirred for an additional 8 h. The reaction mixtureis cooled to room temperature, poured into 200 ml of ice-water,extracted with ethyl acetate (100 ml×3). The combined organics arewashed with water, brine, dried over anhydrous sodium sulfate, filtered,evaporated at reduced pressure and purified by flash chromatography onsilica gel to obtain 9.08 g of 1-butyl-4-phenylimidazole. ¹H NMR (400MHz, CDCl₃) δ 7.77 (2H, d, J=7.6 Hz), 7.49 (1H, s), 7.36 (2H, t, J=7.6Hz), 7.23 (1H, m), 7.20 (1H, s), 3.95 (2H, t, 17.2 Hz), 1.80 (2H, m),1.36 (2H, m), 0.96 (3H, t, J=7.2 Hz); MS (+VE) m/z 201 (M+1).

To a solution of 1-butyl-4-phenylimidazole (4.0 g, 20 mmol) in 60 ml ofanhydrous THF at −78° C. under nitrogen is added a solution ofn-butyllithium in hexane (1.6M, 13.13 ml, 21 mmol, 1.05 eq.) dropwise.The resulting mixture is stirred at −78° C. for 1 h followed by dropwiseaddition of a solution of iodine (5.33 g, 21 mmol, 1.05 eq.) in 40 ml ofTHF. The resulting solution is stirred at −78° C. for 30 min. and thenwarmed to room temperature. Saturated ammonium chloride (30 mL) is addedto quench the reaction. The resulting mixture is evaporated a reducedpressure to remove THF, extracted with ethyl acetate, washed with waterand brine, dried over Na₂-SO₄, filtered and evaporated. Purification bysilica gel chromatography (hexanes/ethyl acetate, from 8:1 to 5:1)affords 5.73 g of butyl-2-iodo-4-phenylimidazole. ¹H NMR (400 MHz,CDCl₃) δ 7.73 (2H, dd, J=1.2, 8.4 Hz), 7.36 (2H, m), 7.30 (1H, s), 7.24(1H, m), 3.91 (2H, t, J=7.2 Hz), 179 (2H, m), 1.41 (2H, m), 0.98 (3H, t,J=7.2Hz); MS (+VE) m/z 327 (M+1).

To a 60 ml sealed flask is added 1-butyl-2-iodo-4-phenylimidazole (3.26g, 10 mmol) followed by the addition of 5.5 ml of acetic acid, 16 ml of37% formaldehyde and 7g of sodium acetate. The resulting mixture isstirred at 115° C. for 10 h, cooled to room temperature and diluted 50ml of water. The reaction mixture is adjusted to pH=9, extracted withethyl acetate, washed with water and brine, dried over Na₂SO₄, filteredand evaporated. Purification by silica gel chromatography (hexanes/ethylacetate, from 8:1 to 2.1) affords 3.24 of1-butyl-5-hydroxymethyl-2-iodo-4-phenylimidazole. ¹H NMR (400 Hz, CDCl₃)δ 7.59 (2H, dd, J=1.6, 6.8 Hz), 7.39 (2H, m), 7.31 (1H, m), 4.78 (2H,s), 4.00 (2H, t, J=8.0 Hz), 1.78 (2H, m), 1.46 (2H, m), 1.00 (3H, t,J=7.2 Hz); MS (+VE) m/z 357(M+1).

1-Butyl-5-hydroxymethyl-2-iodo-4-phenylimidazole (1.96 g, 6.1 mmol) isdissolved in 20 ml dichloromethane and cooled to 0° C. To the solutionis added 5 equivalents of thionyl chloride and the resulting solution isstirred at room temperature for 2 h. The reaction mixture is evaporatedat reduced pressure and 20 ml of toluene is added to the residue andevaporated to remove any residual thionyl chloride. The crude product isdissolved in 20 ml of anhydrous acetonitrile and added to an ice-cooledsolution of piperonyl amine (2.0 eq.) in acetonitrile (10 mL) containingpotassium carbonate (2 eq.). The resulting mixture is stirred at roomtemperature for 4 h, diluted with 100 ml of ethyl acetate, washed withwater and brine, dried over sodium sulfate and concentrated at reducedpressure. The residue is purified by silica gel chromatography(hexanes/ethyl acetate, from 2:1 to 1:1) to give 2.28 g of1-butyl-5-chloromethyl-2-iodo-4-phenylimidazole. MS (+VE) m/z 490 (M+1).

To a solution of 1-butyl-5-chloromethyl-2-iodo-4-phenylimidazole (1.22g, 2.5 mmol) in 1,2-dichloroethane (10 mL) is added piperonal (750 mg,5.0 mmol, 2.0 eq) followed by 10 drops of acetic acid. The solution isstirred at room temperature for 2 h, sodium triacetoxyborohydride (1.1g, 5.0 mmol, 2.0 eq.) is added and the resulting mixture is stirred atroom temperature overnight. The reaction mixture is diluted with 50 mlof dichloromethane, washed with water and brine, dried and concentrated.The residue is purified by silica gel flash chromatography(hexanes/ethyl acetate, from 8:1 to 4:1) to affordbis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-2-iodo-5-phenyl-3H-imidazol-4-ylmethyl)-amine.¹H NMR (400 MHz, CDCl₃) δ 7.57 (2H, m), 7.39 (2H, m), 7.31 (1H, m),6.70-6.73 (4H, m), 6.64 (2H, d, J=8.0 Hz), 5.94 (4H, s), 4.01 (2H, t,J=6.8 Hz), 3.71 (2H, s), 3.32 (4H, s), 1.41 (2H, m), 1.15 (2H, m), 0.88(3H, t, J=7.6 Hz); MS (+VE) m/z 624 (M+1).

To a solution ofbis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-2-iodo-5-phenyl-3H-imidazol-4-ylmethyl)-amine(62 mg, 0.1 mmol) and Pd(PPh₃)₄ (6 mg) in 1 ml of toluene is addedaqueous sodium carbonate (0.4 ml of 2.0 N) and 2-methylphenyl boronicacid (18 mg, 0.13 mmol, 1.3 eq.) in 0.3 ml of ethanol under nitrogen,the resulting mixture is stirred at 100° C. for 8 h. After being cooledto room temperature, the reaction mixture is diluted with 10 ml of ethylacetate, washed with water and brine and dried over sodium sulfate.Concentration and purification by flash chromatography affords 43 mg ofbis-benzo[1,3]dioxol-5-ylmethyl(3-butyl-5-phenyl-2-o-tolyl-3H-imidazol-4-ylmethyl)-amine¹H NMR (400 MHz, CDCl₃) δ 7.70 (2H, d, J=7.2 Hz), 7.43˜7.24 (7H, m),6.77˜6.67 (6H, m), 5.94 (4H, s) 3.87 (2H, t, J=7.6 Hz), 3.78 (2H, s),3.37 (4H, s), 2.20 (3H,s), 1.17 (2H, m), 0.88 (2H, m), 0.63 (3H, t,J=7.2 Hz); MS (+VE) m/z 588 (M+1).

Example 24 Preparation of4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3h-imidazol-4-ylmethyl]-cyclohexylmethyl-amino}-methyl)-2-hydroxy-benzamide

To a solution of benzamidine hydrochloride (31.22 g, 02 mmol, 1.17 eq.)in 250 ml of DMF is added potassium carbonate (69 g, 0.5 mol).2-bromo-4′-methoxyacetophnone is dissolved in 200 ml of DMF and added tothe reaction flask dropwise at 55° C. After the addition, the reactionmixture is stirred at 60° C. for 3 h, then cooled to room temperatureand poured into 1000 ml of ice-water, the mixture is extracted withethyl acetate (150 ml×4), washed with water and brine, dried over sodiumsulfate, purified through flash chromatography to give 30g of2-phenyl-4-(4 methoxyphenyl)imidazole. ¹H NMR (400 MHz, CDCl₃) δ 7.86(2H, d, J=6.8 Hz), 7.43˜7.25 (5H, m), 6.93 (2H, d, 18.8 Hz), 3.83 (3H,s); MS (+VE) m/z 251 (M+1).

Potassium hydroxide (4.36, 76 mmol, 1.3 eq.) is suspended in 40 ml ofanhydrous DMSO, to the suspension is added a solution2-phenyl-4-(4-methoxyphenyl)imidazole (15.02, 60 mmol) and bromobutane(8.63 g, 63 mmol, 1.05 eq.) in 80 ml of DMSO at room temperature over2h, the resulting mixture is stirred over 24h, and then poured into 400ml of ice-water, extracted with ethyl acetate (100 ml×4), washed,withwater and brine, dried over anhydrous sodium sulfate. The solvent isevaporated and the product is purified through flash chromatography togive 16.73 g of 4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazole.MS (+VE) m/z 307 (M+1).

To a 150 ml sealed flask is added4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H -imidazole (10.72, 35mmol) followed by the addition of 24 ml of acetic acid and 24 ml of 37%formaldehyde, the resulting mixture is stirred at 70° C. for 8 h, thencooled to room temperature. The organic solvents is evaporated, theresidue is diluted 100 ml of water and basified with sodium hydroxidesolution, the mixture is extracted with ethyl acetate (100 ml×4), washedwith water and brine, dried over Na₂SO₄. Concentration and purificationthrough silica gel chromatography (hexanes/ethyl acetate, from 8:1 to1:1) affords 10.0 of4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethanol aswhite solid. ¹H NMR (400 MHz, CDCl₃) δ 7.58 (2H, dd, J=8.7 Hz),7.354˜7.51 (2H, m), 7.44˜7.38 (3H, m), 6.87 (2H, d, J=8.7 Hz), 4.59 (2H,s), 3.95 (2H, t, J=7.5 Hz), 3.784 (3H, s), 1.60 (2H, m), 1.16 (2H, m),0.77 (3H, t, J=7.2 Hz); MS (+VE) m/z 337 (M+1).

4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethanol(6.72 g, 20 mmol) is dissolved in 30 ml dichloromethane and cooled to 0°C., to the solution is added 5 equivalent of thionyl chloride. Theresulting solution is stirred at room temperature for 2 h, the solventand excess of thionyl chloride is evaporated. 20 ml of toluene is addedto the residue and evaporated again to remove the remained thionylchloride. The residual crude product is dissolved in 30 ml of anhydrousacetonitrile and added to an ice-cooled solution of cyclohexanemethylamine (2.0 eq.) in 20 ml of acetonitrile containing, 2 equivalent ofpotassium carbonate. The resulting mixture is stirred at roomtemperature for 4 h, then diluted with 200 ml of ethyl acetate, washedwith water and brine, dried and concentrated, the residue is purifiedthrough silica gel chromatography (hexanes/ethyl acetate, from 2:1 to1:1) to give 11.26 g of4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethyl]-cyclohexylmethyl-amine.¹H NMR (400 MHz, CDCl₃) δ 7.64˜7.60 (4H, m), 7.47˜7.40 (3H, m), 6.94(2H, d, J=8.8 Hz), 4.11 (2H, m), 3.87 (2H, s), 3.84 (3H,s), 2.52 (H, d,J=6.4 Hz), 0.91˜1.77 (15H, m), 0.84 (3H, t, J=7.2 Hz); MS (+VE) m/z 432(M+1).

To a solution of4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethyl]-cyclohexylmethyl-amine(4.0 g, 9.31 mmol) and 3-acetoxyl-4-tert-butoxycarbonyl-benzyl bromide(3.37 g, 10.24 mmol, 1.1 eq.) in 50 ml anhydrous acetonitrile is addedanhydrous potassium carbonate (2.82 g, 20.5 mmol, 2.2 eq.), theresulting mixture is stirred at room temperature for 1 h, then raised to50° C., stirred overnight. The solid precipitate is filtered off, washedwith ethyl acetate, the combined organics is concentrated to dryness,purified through silica gel flash chromatography to give 3.99 g of4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethyl]cyclohexylmethyl-amino}-methyl)-2-acetoxy-benzoicacid tert-butyl ester MS (+VE) m/z 680 (M+1).

4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethyl]-cyclohexylmethyl-amino}-methyl)-2-acetoxy-benzoicacid tert-butyl ester (3.99 g, 5.87 mmol) is dissolved in 50 ml ofdichloromethane, to the solution is added 10 ml of Trifluoroacetic acidat 0° C., after stirring at room temperature for 8 h, the solvent isevaporated under house vacuum and the residue is dissolved in 30 ml oftoluene (containing 5 ml of THF), to the solution is added 6 equivalentof thionyl chloride at 0° C., and then the reaction mixture is heated to60° C., stirred overnight. The solvent and the remained thionyl chlorideis evaporated, the residue is dissolved in 50 ml of chloroform and addedto concentrated aqueous ammonium hydroxide solution with vigorousstirring slowly, stirred for 4 h. The chloroform layer is collected, andthe aqueous phase is extracted with chloroform (50 ml×2), the combinedorganics is evaporated to dryness, and the residue is dissolved in 60 mlof methanol followed with addition of 30 ml of saturated aqueous sodiumbicarbonate solution and 30 ml of water, the mixture is stirred at40-45° C. overnight. The methanol is evaporated, and the residue isextracted with dichloromethane (50 ml×3), dried over sodium sulfate.Concentration and purification through silica gel flash chromatographyaffords 2.74 g of4-({[3-butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-1-imidazol-4-ylmethyl]-cyclohexylmethyl-amino}-methyl)-2-hydroxy-benzamide.¹H NMR (400 MHz, CDCl₃) δ 7.57 (2H, d, J:=8.7 Hz), 7.39˜7.51 (5H, m),7.27 (H, d, J=8.1 Hz), 6.95 (2H, d, J=9.0 Hz), 6.88 (1H,d, J=1.5Ha),6.57 (1H, dd, J=1.5, 8.4 Hz), 4.15 (2H, m), 3.84 (3H, s), 3.71 (2H, s),3.36 (2H, s), 2.19 (2H, d, J=6.9 Hz), 0.77˜1.80 (15H, m), 0.70 (3H, t,J=6.9 Hz); MS (+VE) m/z 581 (M+1).

Example 25 Preparation of(3-Butyl-5-chloro-2-O-tolyl-3H-1-imidazol-4-ylmethyl)-(3-chloro-1H-indol-5-ylmethyl)-(3-methyl-butyl)-amine

To a solution of(3-Butyl-5-chloro-2-o-tolyl-3H-imidazol-4-ylmethyl)-(1H-indol-5-ylmethyl)-(3-methyl-butyl)-amine(150 mg, 0.31 mmol) in 5 ml of anhydrous acetonitrile cooled to 0° C. isadded NCS (44 mg, 0.33 mmol, 1.05 eq.), the resulting mixture is stirredat 40° C. overnight. The solvent is evaporated; the residue is purifiedthrough flash chromatography to give 112 mg of(3-butyl-5-chloro-2-o-tolyl-3H-imidazol-4-ylmethyl)-(3-chloro-1H-indol-5-ylmethyl)-(3-methyl-butyl)-amineas a white solid. ¹H NMR (400 MHz, CDCl₃) δ 9.39 (1H, S), 7.52 (1H, S),7.11˜7.36 (6H, m), 6.98 (1H, d, J=2.4 Hz), 3.67 (2H, m), 3.65 (2H, s),3.54 (2H, s), 2.52 (2H, t, J=7.2 Hz), 2.11 (3H, s), 1.62 (1H, m), 1.45(2H, q, J=6.9 Hz), 1.10 (2H, m), 0.84 (6H, d, J=6.6 Hz), 0.73 (2H, m),0.47 (3H, t, J=6.9 Hz); MS (+VE) m/z 511 (M+1).

Example 26 Preparation of5-{[(3-Butyl-5-chloro-2-O-tolyl-3H-imidazol-4-ylmethyl)-(3-methyl-butyl)-amino]-methyl}-1H-indole-3-carbonitrile

To an ice-cooled solution of5-{[(3-butyl-5-chloro-2-o-tolyl-3H-imidazol-4-ylmethyl)-(3-methyl-butyl)-amino]-methyl}-1H-indole(173 mg, 0.363 mmol) in 5 ml of anhydrous acetonitrile under nitrogen isadded a solution of chlorosulfonyl isocyanate (69.5 mg, 0.491 mmol, 1.35eq.) in 1 ml of acetonitrile, after stirring for 20 mim, a solution ofDMF (30.1 mg) in 2 ml of acetonitrile is added dropwise, stirred foradditional 1 h. The reaction mixture is poured into ice water andbasified with diluted ammonium hydroxide solution; the mixture isextracted with dichloromethane, dried over sodium sulfate. The solventis evaporated; the residue is purified through flash chromatography togive 11 mg of5-{[(3-butyl-5-chloro-2-o-tolyl-3H-imidazol-4-ylmethyl)-(3-methyl-butyl)-amino]-methyl}-1H-indole-3-carbonitrileas white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.63 (1H, s), 7.38 (1H, d,J=3Hz), 7.15˜7-36 (4H, m), 7.07 (4H, dd, J=1.2, 8.4 Hz), 6.89-6.93 (2H,m), 3.73 (2H, t, J=7.5 Hz), 3.65 (2H, s), 3.57 (2H, s), 2.55 (2H, d,f=6.9 Hz), 2.02 (3H, s), 1.62 (1H, m), 1.46 (2H, q, J=6.6 Hz), 1.14 (2H,m), 0.85 (6H, d, J=6.6 Hz), 0.75 (2H, m), 0.51 (3H, t, J=7.2 Hz); MS(+VE) m/z 502 (M+1).

Example 27 Preparation of(R)-[1-(3-Butyl-2-phenyl-3H-imidazole-4-yl)-pentyl]-cyclohexylmethyl-(4-methoxy-benzyl)-amine

(R)-(3-Butyl-2-phenyl-3H-imidazole-4-ylmethylene)-(2-methoxymethyl-pyrrolidin-1-yl)-amine(192). A solution of aldehyde 138 (4.05 g, 14 mmol) and SAMP (2 g, 15mmol) in benzene is refluxed for 15 h with Dean-Stark trap under argon.The solvent is then removed and the residue is used for the next stepwithout further purification. LC-MS (MH+): 341.

(R,S)-[1-(3-Butyl-2-phenyl-3H-imidazole-4-yl)-pentyl]-(2-ethoxymethyl-pyrrolidin-1-yl)-amine(193). To a solution of BuLi (2.5 M in hexane, 12.5 ml, 31 mmol) underargon in anhydrous THF (15 mL) at −78° C. is slowly added a solution ofcrude 192 (14 mmol) in TEF (15 mL). The mixture is allowed to warm toroom temperature over a period of 15 h and quenched with saturatedsodium bicarbonate. The aqueous phase is extracted with ethyl acetateand the combined organic phases were washed with water and dried oversodium sulfate. Removal of solvents under reduced pressure andpurification of the residue by column chromatography affords the desiredproduct as a colorless syrup. Yield: 5.1 g; [α]_(D)-72 (c=1.2, CHCl₃);LC-MS (MH+): 399.

(R)-1-(3-Butyl-2-phenyl-3H-imidazol-4-yl)-pentylamine (194). To asolution of 193 (1.43 g, 3.6 mmol) under argon in anhydrous THF (25 mL)at room temperature is slowly added borane-THF complex (1 M in THF, 54ml, 54 mmol). The mixture is then refluxed under argon for 16 h. Aftercooling to room temperature, 10% HCl (20 mL) is added very slowly andthe mixture is stirred for 2 h at room temperature. The organic solventis removed under reduced pressure and the residue is extracted withether. The aqueous phase is saturated with solid potassium carbonate andextracted with sthyl acetate. The residue obtained after removal of thesolvent is purified by column chromatography to afford the desiredproduct as a colorless oil. Yield: 0.6 g; LC-MS (MH+): 286.

(R)-[1-(3-Butyl-2-phenyl-3H-imidazol-4-yl)-pentyl]-cyclohexylmethylene-amine(196) and[1-(3-butyl-2-phenyl-3H-imidazol-4-yl)-pentyl]-cyclohexylmethyl-amine(197). A solution of amine 194 (440 mg, 1.54 mmol) andcyclohexylmethylaldehlyde (173 mg, 1.6 mmol) in benzene is refluxed for16 h with Dean-Stark trap under argon. The solvent is then removed andthe residue 196 is used for the next step without further purification.LC-MS (MH+): 380. The crude 196 is dissolved in anhydrous methanol (10mL) and cooled to 0° C. To this solution, sodium borohydride (80 mg) isadded slowly and the mixture is stirred at room temperature for 4 h. Thereaction is quenched with water (10 mL) and most methanol is removedunder reduced pressure. The residue is extracted with ethyl acetate, andthe organic phase is washed with saturated sodium bicarbonate and brine.Evaporation of the solvent and purification of the residue affords acolorless oil. Yield: 560 mg; [α]_(D)-5.8 (c=1, CHCl₃); LC-MS (MH+):382.

(R)-[1-(3-Butyl-2-phenyl-3H-imidazole-4-yl)-pentyl]-cyclohexylmethyl-(4-methoxy-benzyl)-amine(199). This compound is prepared from amine 197 and aldehyde 198 in themanner as described in Example 9 for preparation of compound 145. Theenantiomer excess value of 199 is greater than 97.5% identified bychiral column, [α]_(D)-14.4 (c=1, CHCl₃); LC-MS (MH+): 502; ¹H NMR (400MHz, CDCl₃) δ 7.46-7.37 (m, 3H), 7.28 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.4Hz, 2H), 6.99 (s, 1H), 6.89-6.84 (m, 2H), 3.80 (s, 2H), 3.78 (s, 2H),3.76-3.61 (m, 5H), 2.38-2.32 (m, 1H), 2.17-2.22 (m, 1H), 1.98-1.94 (m,2H), 1.70-1.52 (m, 5H), 1.46-1.34 (m, 4H), 1.26-0.99 (m, 6H), 0.95 (t,J=7.2 Hz, 3H), 0.82-0.71 (m, 2H), 0.58 (t, J=7.2 Hz, 3H).

Example 28 Preparation of(S)-[1-(3-Butyl-2-phenyl-3H-imidazole-4-yl)-pentyl]-clyclohexylmethyl-(4-methoxy-benzyl)-amine

The title compound 200 is prepared in the same manner as in Example 20using RAMP. The analytical data is intentical to that of compound 199except for the optical rotation.

Example 29 Preparation of(R)-4({Butyl-[1-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-ethyl]-amino}-methyl)-benzamide

(R)-4({Butyl-[1-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-ethyl]-amino}-methyl)-benzoicacid (202). This compound is prepared in the same manner as in Example20 sing aldehyde 201 as the starting material. 4-formylbenzoic acid isemployed for the reductive amination step. LC-MS (MH+): 510.

(R)-4({Butyl-[1-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-ethyl]-amino}-methyl)-benzamide(204). A solution of compound 202 (110 mg, 0.2 mmol) in anhydrouschloroform is treated with thionyl chloride (0.2 mL) under reflux for 2h. The solvent and excess of thonyl chloride were evaporated underreduced pressure and the residue is dried in vacuo to yield acidchloride 203 which is used for the next step without furtherpurification. To a vigorously stirred solution of ammonium hydroxide(30% in water, 2 ml) and chloroform (4 mL) is added a solution of 203 inchloroform (2 mL) in one portion at room temperature. The mixture iscontinued stirring at room temperature overnight. The organic phase isseparated and the aqueous phase is extracted with dichloromethane. Thecombined organic phase is washed with water, saturated sodiumbicarbonate and brine. Removal of the solvent and purification of theresidue by column chromatography yields the desired product 204. Yield:98 mg. LC-MS (MH+): 509; ¹H NMR (300 MHz, CDCl₃) δ 7.71 (d, J=7.8 Hz,2H), 7.60 (d, J=7.8 Hz, 2H), 7.50-7.48 (m, 2H) 7.40-7.38 (m, 4H), 7.32(d, J=7.5 Hz, 1H), 726 (d, J=7.8 Hz, 2H), 6.12 (br s, 1H), 5.75 (br s,1H), 4.55-4.45 (m, 1H), 4.27 (q, J=6.9 Hz, 1H), 4.14-4.03 (m, 1H), 3.71(d, J=14.7 Hz, 1H), 3.52 (d, J=14.7 Hz, 1H), 2.53 (d, J=7.4 Hz, 2H),2.05-1.96 (m, 2H), 1.49 (d, J=6.9 Hz, 3H), 1.44-1.13 (m, 4H), 0.88-0.75(m, 6H).

Examples 29-40 Preparation of Various 4-Substituted ImidazoleDerivatives

Example 29 Preparation ofBis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-5-dimethoxymethyl-2-phenyl-3H-imidazol-4-ylmethyl)amine(212)

3-Bromo-1,1-dimethoxy-propan-2-one (206). Bromine (80 g, 0.5 mol) isadded dropwise to a solution of 1,1-dimethoxy-propan-2-one 205 (59 g,0.5 mol) in anhydrous methanol (400 mL) at 0° C. and the solution iscontinued stirring at room temperature for 48h. The solvent is removedunder reduced pressure and the residue is dried in vacuo and usedwithout further purification.

4-Dimethoxymethyl-2-phenyl-1H-imidazole (208). To a solution ofbenzamidine 207 (1.44 g, 12 mmol) and potassium carbonate (4.1 g, 30mmol) in anhydrous DMF (25 mL) is slowly added a solution of3-bromo-1,1-dimethoxy-propan-2-one 206 (1.97 g, 10 mmol) in anhydrousDMF (10 mL) over 30 min. The mixture is then heated at 50-60° C. for 2h. After cooling to room temperature, ethyl acetate (100 mL) and water(100 mL) were added. The organic phase is separated and the aqueousphase is extracted with ethyl acetate twice and the combined organicphase is washed with water (3×20 mL) and brine. Removal of solventsunder reduced pressure and purification of the residue by columnchromatography affords the desired product as a white solid. Yield: 2.08g; LC-MS (MH+): 219. ¹H NMR (300 MHz, CDCl₃) δ 7.88-7.85 (m, 2H),7.37-7.46 (m, 4H), 5.49 (s, 1H), 3.36 (s, 6H).

1-Butyl-4-dimethoxymethyl-2-phenyl-TH-imidazole (209). A solution of4-dimethoxymethyl-2-phenyl-1H-imidazole 208 (2.18 g, 10 mmol) andn-butyl bromide (2.74 g, 20 mmol) in anhydrous DMSO (15 mL) is added toa suspension of powdered potassium hydroxide (0.96 mg, 15 mmol) in DMSO(20 mL) at room temperature over 3 h. The mixture is then stirred at rtfor 16 h. The mixture is diluted with ether and washed with water (threetimes), brine, and dried over anhydrous sodium sulfate. Removal of thesolvent and purification of the residue affords the desired product.Yield: 2.5 g; LC-MS (MH+): 275.

3-Butyl-5-dimethoxymethyl-2-phenyl-3H-imidazole-4-carbaldehyde (210). Toa solution of 1-butyl-4-dimethoxymethyl-2-phenyl-1H-imidazole 209 (2.74g, 10 mmol) in anhydrous TH-F under nitrogen at −78° C., n-BuLi (1.6 Min hexane, 7.5 ml, 12 mmol) is added dropwise and the mixture iscontinued stirring at this temperature for 30 ran. After anhydrous DMF(4 mL) is added, the mixture is stirred at room temperature for 16 h.Saturated ammonium chloride and ethyl acetate were added at 0° C. andthe organic phase is separated. The aqueous phase is extracted withethyl acetate and the combined organic phase is washed with brine, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue is purified by column chromatography to yield the desiredproduct as a white solid. Yield: 1.94 g; LC-MS (MH+): 303. ¹H NMR (300MHz, CDCl₃) δ 10.18 (s, 1H), 7.60-7.56 (m, 2H), 7.51-7.46 (m, 3H), 5.63(s, 1H), 4.32 (t, J=6.3 Hz, 2H), 3.47 (s, 6H), 1.73-1.63 (m, 2H),1.28-1.16 (m, 2H), 0.82 (t, J=7.2 Hz, 3H).

Benzo[1,3]dioxol-5-ylmethyl-(3-butyl-5-dimethoxymethyl-2-phenyl-3H-imidazol-ylmethyl)-amine(211). A solution of3-butyl-5-dimethoxymethyl-2-phenyl-3H-imidazole-4-carbaldehyde (2.1 g, 7mmol) and piperalamine (7 mmol) in anhydrous methanol (35 mL) is stirredat room temperature overnight. After cooling to 0° C., sodiumborohydride (7 mmol) is added slowly in 30 min. The reaction is quenchedby addition of water (20 mL) and most methanol is removed under reducedpressure. The residue is extracted with ethyl acetate and washed withwater and brine, dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue is purified by column chromatographyto yield the desired product as a colorless syrup Yield: 2.62 g; LC-MS(MH+): 438.

Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-5-dimethoxymethyl-2-phenyl-3H-imidazol-4-ylmethyl)amine(212). This compound is prepared according to the procedure aspreparation of 129 in Example 7. LC-MS (MH+): 572.

Example 30 Preparation of5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-carbaldehyde(213)

Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-5-dimethoxymethyl-2-phenyl-3H-imidazol-4-ylmethyl)amine212 (571 mg, 1 mmol) in THF (5 mL) is treated with p-toluenesulfonicacid monohydrate (380 mg, 2 mmol) at room temperature overnight. Thesolvent is removed and the residue is diluted with ethyl acetate andwashed with saturated sodium bicarbonate and brine. The solvent isremoved under reduced pressure and the redure is purified by columnchromatography to yield the desired product. Yield: 510 mg; LC-MS (MH+):526.

Example 315-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-carboxylicacid (214)

To a solution of5-[(bis-benzo[1,3]dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-carbaldehyde213 (263 mg, 0.5 mmol) in actone (10 mL) and water (5 mL) is addedsulfamic acid (107 mg, 1.1 mmol) at room temperature and the mixture isstirred for 30 min. Sodium chlorite (63 mg, 0.7 mmol) is added and themixture is stirred for additional 30 men at room temperature.Evaporation of most actone and the residure is extracted withchloroform. The organic phase is washed with water, brine and dried oversodium sulfate. The solvent is removed aid the product is dried invacuo. Yield: 281 mg; LC-MS (MH+): 542.

Example 325-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-carboxylicacid methyl ester (215)

To a solution of5-[(bis-benzo[1,3]dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-carboxylicacid 214 (54 mg, 0.1 mmol) in methanol (5 mL) at 0° C. is added freshlyprepared diazomethane ether solution. The mixture is stirred for 1 h andconcentrated to provide the desired methyl ester. LC-MS (MH+): 556.

Example 332-{5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-yl}-propan-2-ol(216)

To a solution of5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-carboxylicacid methyl ester 215 (40 mg, 0.08 mmol) in anhydrous THF (2 mL) at −78°C. under argon is added methyl lithium (1M solution in ether, 0.2 ml,0.2 mmol). The mixture is then stirred at room temperature for 1 h andthe reaction is quenched with saturated ammonium chloride. The residureis extracted with ethyl acetate, washed with brine, dried over sodiumsulfate, concentrated and purified by column chromatography to yield thedesired product. Yield: 35 mg; LC-MS (MH+): 556.

Example 34{5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-yl}-methanol(217)

To a solution of5-[(bis-benzo[1,3]dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-carbaldehyde 213 (52 mg, 0.1 mmol) in anhydrous methanol (5mL) at room temperature is added sodium borohydride (10 mg) and themixture is stirred for 30 min. Water is added to quench the reaction andthe residure is extracted with ethyl acetate. The organic phase iswashed with water, brine and dried over sodium sulfate. The solvent isremoved and the residue is purified by column chromatography to yieldthe desired product. Yield: 51 mg; LC-MS (MH+): 528.

Example 35Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-5-methoxymethyl-2-phenyl-1H-imidazol-4-ylmethyl)-amine(218)

To a solution of{5-[(bis-benzo[1,3]dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-yl}-methanol217 (52 mg, 0.1 mmol) and NaH (5 mg) in anhydrous THF (5 mL) at 0° C.under argon is added iodomethane (0.05 mL) and the mixture is stirredfor 1 h. Evaporation of the solvent and excess of MeI and the residue ispurified by column chromatography to yield the desired product. Yield:41 mg; LC-MS (MH+): 542.

Example 36Bis-benzo[1,3]dioxol-5-ylmethyl-(1′-butyl-2′-phenyl-1′H-[1,4′]biimidazolyl-5′-ylmethyl)-amine(219)

To a solution of{5-[(bis-benzo[1,3]dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-yl}-methanol217 (52 mg, 0.1 mmol) in anhydrous acetonitrile (5 mL) at roomtemperature is added CDT (21 mg, 0.13 mmol) and the mixture is stirredfor 1 h. Evaporation of the solvent and excess of MeI and the residue ispurified by column chromatography to yield the desired product. Yield:561 mg; LC-MS (MH+) 578.

Example, 371-{5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino)-methyl]-1-butyl-2-phenyl-1H-imidazol-4-Yl}ethanol(220)

This compound is prepared in the manner as described for the preparationof 216 to yield the desired product; LC-MS (MH+): 542.

Example 381-{5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino)-methyl]-1-butyl-2-phenyl-1H-imidazol-4-yl}ethnone(221)

A solution of1-{5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino)-methyl]-1-butyl-2-phenyl-1H-imidazol-4-yl}-ethanol220 (54 mg, 0.1 mmol) in anhydrous THF (5 mL) is oxidized with MnO₂ (100mg) under reflux for 5 h. After cooling to room temperature, the residueis filtered though celite and concentrated. The residue is purified bycolumn chromatography to yield the desired product. Yield: 38 mg; LC-MS(MH+): 540.

Example 39Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-5-dimethylaminomethyl-2-phenyl-3H-imidazol-4-yl}-amine(222)

This compound is prepared in the manner as described for the preparationof 212 to yield the desired product; LC-MS (MH+): 542.

Example 395-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino)-methyl]-1-butyl-2-phenyl-1H-imidazole-4-carboxyliacid dimethylamide (223)

To a solution of5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino]1-butyl-2-phenyl-1H-imidazol-4-carboxylicacid 214. (50 mg, 0.1 mmol) in anhydrous dichloromethane (3 mL) is addeddimethylamine (1M solution in THF, 0.4 ml, 0.4 mmol) and DCC (0.2 mmol)and the mixture is stirred for 48 h. Evaporation the solvent and theresidue is purified by column chromatography to yield the desiredproduct. Yield-25 mg; LC-MS (MH+): 569.

Example 40Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-5-difluoromethyl-2-phenyl-1H-imidazol-4-ylmethyl)-amine(224)

To a solution of5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-carbaldehyde213 (42 mg, 0.8 mmol) in anhydrous dichloromethane (2 mL) at −78° C.under argon is added DAST (0.11 ml, 8.1 mmol). The mixture is stirred atroom temperature for 16 h and concentrated. The residue is purified bycolumn chromatography to yield the desired product. Yield: 33 mg; LC-MS(MH+): 548.

Example 41 Preparation of2-(2,6-diethylphenyl)-4-chloroimidazole-5-carboxyaldehyde Synthesis of2,6-diethylphenylboronic acid

2,6-Diethyl bromobenzene (38.2 g, 180.2 mmol) is added dropwise throughan additional funnel over a 1 hour period to a solution of n-BuLi (2.0 Min cyclohexane, 99.1 ml, 198.2 mmol) in THF (380 mL) at −75° C. Afteraddition, the reaction mixture is stirred at −75° C. for 30 minutes;trimethyl borate (28.1 g, 270.3 mmol) is added slowly over a 40 minuteperiod. The reaction mixture is warmed to room temperature overnight. 2NHCl (250 mL) is added slowly and the resulting mixture is stirred for 1hour. The organic layer is separated and the aqueous layer is extractedwith ether (2×200 mL). The combined organic layers are dried overanhydrous Na₂SO₄ and the solvents are removed in vacuo. Hexane (400 mL)is added to the residue and a white precipitate is formed. Filtrationand drying in vacuo gives 19.0 g of 2,6-diethylphenyl boronic acid as awhite solid. ¹H NMR: (CDCl₃) 7.22 (t, 1H), 7.04 (s, 2H), 4.65 (s, 2H),2.64 (q, 4H), 1.22 (t, 6H).

Synthesis of 1-Methoxyethyl-3,4-dichloroimidazole

A solution of 1 mmol of 3,4-dichloroimidazole in anhydrous DMF (5 n-L)is treated with sodium hydride (1.05 mmol) at 0° C. under nitrogen withmagnetic stirring. After 30 min., 2-chloroethyl methyl ether (1 mmol) isadded and the reaction mixture is warmed to 60° C. for 2 h. The reactionmixture is cooled, portioned between water and ethyl acetate. Theorganic layer is separated, washed with water, brine and dried oversodium sulfate. The reaction mixture is filtered, evaporated andpurified by chromatography on silica gel to obtain1-methoxyethyl-3,4-dichloroimidazole.

Synthesis of 2-bromo-1-methoxyethyl-3,4-dichloroimidazole

To a solution of 1-methoxyethyl-3,4-dichloroimidazole (1.95 g, 10 mmol)in acetonitrile (50 mL) is added NBS (1.86 g, 1.05 mmol) at roomtemperature in portions. The reaction mixture is stirred at rt for 30min. Ethyl acetate (100 ml) is added and washed with water, brine, driedover MgSO₄, filtered and evaporated in vacuo to dryness. The crudeproduct is purified by flash chromatography (hexane/ethyl acetate 100/5)to obtain 2-bromo-1-methoxyethyl-3,4-dichloroimidazole.

Synthesis of 2-(2,6-diethylphenyl)-1-methoxyethyl-3,4-dichloroimidazole

A solution containing 2-bromo-in-methoxyethyl-3,4-dichloroimidazole(2.74 g, 10 mmol), 2,6-diethylphenylboronic acid (2.14 g, 12 mmol.) andPd(PPh₃)₄ (0.23 mg 0.2 mmol) in toluene/2M Na₂CO₃ (30 ml/15 mL) in asealed tube is degassed, then allowed to heat to 110° C. overnight. Theorganic layer is separated and concentrated in vacuo to dryness. Theresidue is purified by column chromatography on silica gel (hexane/ethylacetate 100/5) to obtain the2-(2,6-diethylphenyl)-1-methoxyethyl-3,4-dichloroimidazole.

Synthesis of2-(2,6-diethylphenyl)-1-methoxyethyl-4-chloro-imidazole-3-carboxaldehyde

To a solution of N-methoxyethyl 2-(2,6-diethylphenyl)-1-methoxyethyl-354-dichloroimidazole (3.27 g, 10 mmol) in anhydrous THF is added n-BuLi(1.6M in hexane) (9.4 ml, 15 mmol) dropwise at −78° C. After thereaction mixture is stirred at −78° C. for 2 h, anhydrous DMF (3 equiv.)is added in one portion. The mixture is stirred at −78° C. for 30 min,then allowed to warm to room temperature slowly. The reaction mixture isquenched with water and extracted with ethyl acetate, dried over MgSO₄,filtered, concentrated in vacuo and purified by chromatography on silicagel to give2-(2,6-diethylphenyl)-1-methoxyethyl-4-chloro-imidazole-3-carboxaldehyde.This material is used to make various compounds of Formula I as depictedin Scheme 10 and further illustrated in Examples 4-9 and relatedexamples.

Example 42 Pharmaceutical Preparations of Oral and IntravenousAdministration

A. Tablets containing a C5a antagonist and an anti-arthritic agent whichis not a C5a receptor antagonist can be prepared as illustrated below:

Ingredient Amount C5a receptor antagonist 5 mg-500 mg C5areceptor-inactive therapeutic agent 1 mg-500 mg diluent, binder,distigrant, lubricant excipients q.s. 200-400 mg.B. Tablets containing a C5a receptor antagonist as the only activeingredient can be prepared as illustrated below:

Ingredient mg mg C5a receptor antagonist 10 50 MicrocrystallineCellulose 70.4 352 Grannular Mannitol 15.1 75.5 Croscarmellose Sodium3.0 15.0 Colloidal Silicon Dioxide 0.5 2.5 Magnesium Stearate(Impalpable Powder) 1.0 5.0 Total (mg) 100 500C. Tablets containing a C5a receptor antagonist and a C5a receptorinactive agent may be prepared as follows:

Ingredient mg mg C5a receptor antagonist 10 25 C5a receptor inactivetherapeutic agent 10 25 Microcrystalline Cellulose 40 100 Modified foodcorn starch 1.05 4.25 Magnesium sterate 1.25 0.5D. Intravenous formulations containing a C5a receptor antagonist and aC5a receptor inactive agent may be prepared as follows.

Ingredient Amount C5a receptor antagonist 0.5-10 mg C5a receptorinactive therapeutic agent 0.5-10 mg Sodium Citrate 5-50 mg Citic Acid1-15 mg Sodium Chloride 1-8 mg Water for Injection to 1.0 literE. Oral suspensions containing a C5a receptor antagonist and a C5areceptor inactive agent may be prepared as follows:

Ingredient Amount per 5 ml dose C5a receptor antagonist 5-100 mg C5areceptor inactive therapeutic agent 5-100 mg Polyvinylpyrrolidone 150 mgPoly oxyethylene sorbitan monolaurate 25 mg Benzoic Acid 10 mg to 5 mLwith sorbitol solution (70%)

Example 43 Additional C5a Modulators

Additional compounds of the invention, shown in Tables I-IV are preparedvia the methods provided in Scheme 1-11 and further illustrated inExamples 1-41. Compounds which have an asterisk in the column labeledCa²⁺ Mobilization Assay Ki<1 uM, were tested in the standard assay ofC5a receptor mediated calcium mobilization given in Example 35 and foundto exhibit a Ki of less than 1 uM.

The LC/MS data presented in Tables I-IV were obtained using thefollowing instrumentation and methods. MS spectroscopy data isElectrospray MS, obtained in positive ion mode, with a 15V Cone voltage,using a WATERS ZMD 2000 Mass Spec Detector, equipped with a WATERS 600pump, WATERS 2487 Dual Wavelength Detector, GILSON 215 Autosampler, anda GILSON 841 Microinjector. MassLynx version 3.4 software was used fordata collection and analysis.

Sample, 2-20 uL, was injected onto a 33×4.6 mm YMC ProPack C18;5ucolumn, and eluted using a 2-phase linear gradient at a 4 mL/minute flowrate. Sample was detected at 220 and 254 nm. The elution conditions wereas follows: Mobile Phase A-95/5/0.1 Water/Methanol-TFA, Mobile PhaseB-5/95/0.1 Water/Methanol/TFA.

Gradient- time(min) % B 0 10 0.01 10 2.0 100 3.5 100 3.51 10 3.52

The total run time for the gradient was 4.0 minutes.

TABLE I CMP # STRUCTURE Ca²⁺ Mob. IUPAC Name MASS Ret. Time 225

* 1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1-butyl-4-(methylthio)-2-phenyl-1H- imidazol-5-yl]methyl}methanamine543.22 1.22 226

* 1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1-butyl-4-(methylsulfonyl)-2-phenyl- 1H-imidazol-5-yl]methyl} methanamine575.21 1.27 227

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(methylsulfonyl)-2-phenyl-1H-imidazol-5-yl]methyl}-N-[4- (difluoromethoxy)benzyl] methanamine597.21 1.27 228

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(4-methoxyphenyl)-2-phenyl-1H-imidazol-5-yl]methyl} -N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]methanamine 675.27 1.23 229

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(4-methoxyphenyl)-2-phenyl-1H-imidazol-5-yl]methyl}- N-(3-ethoxybenzyl)methanamine 603.311.24 230

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(4-ethoxyphenyl)-2-phenyl-1H-imidazol-5-yl]methyl}-N-[3- (1,1,2,2-tetrafluoroethoxy)benzyl]methanamine 689.29 1.24 231

* 1-(1,3-benzodioxol-5-yl)-N-({1- butyl-4-[4-(methylthio)phenyl]-2-phenyl-1H-imidazol-5-yl}methyl)- N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]methanamine 691.25 1.24 232

* 1-(1,3-benzodioxol-5-yl)-N-({1- butyl-4-[4-(ethylthio)phenyl]-2-phenyl-1H-imidazol-5-yl}methyl)- N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]methanamine 233

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-methoxyphenyl)-2-phenyl-1H-imidazol-5-yl]methyl}- N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]methanamine 675.27 1.23 234

* 1-(1,3-benzodioxol-5-yl)-N-[{1- butyl-4-(3-ethoxyphenyl)-2-phenyl-1H-imidazol-5-yl]methyl}-N- [3-(1,1,2,2-tetrafluoroethoxy)benzyl]methanamine 689.29 1.24 235

* 1-(1,3-benzodioxol-5-yl)-N-({1- butyl-4-[3-(methylthio)phenyl]-2-phenyl-1H-imidazol-5-yl}methyl)-N- [3-(1,1,2,2-tetrafluoroethoxy)benzyl]methanamine 691.25 1.24 236

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-methylphenyl)-2-phenyl-1H-imidazol-5-yl]methyl}-N- [3-(1,1,2,2-tetrafluoroethoxy)benzyl]methanamine 659.28 1.24 237

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(4-methylphenyl)-2-phenyl-1H-imidazol-5-yl]methyl}-N- [3-(1,1,2,2-tetrafluoroethoxy)benzyl]methanamine 659.28 1.22 238

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3,4-dimethylphenyl)-2-phenyl-1H-imidazol-5-yl]methyl}-N- [3-(1,1,2,2-tetrafluoroethoxy)benzyl]methanamine 673.29 1.25 239

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3,5-dimethylphenyl)-2-phenyl-1H-imidazol-5-yl]methyl}-N- [3-(1,1,2,2-tetrafluoroethoxy)benzyl]methanamine 673.29 1.27 240

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-fluorophenyl)-2-phenyl-1H-imidazol-5-yl]methyl}-N- [3-(1,1,2,2-tetrafluoroethoxy)benzyl]methanamine 663.25 1.23 241

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(4-fluorophenyl)-2-phenyl-1H-imidazol-5-yl]methyl}-N- [3-(1,1,2,2-tetrafluoroethoxy)benzyl]methanamine 663.25 1.22 242

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3,4-difluorophenyl)-2-phenyl-1H-imidazol-5-yl]methyl}-N- [3-(1,1,2,2-tetrafluoroethoxy)benzyl]methanamine 681.24 1.24 243

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-methylphenyl)-2-phenyl-1H-imidazol-5-yl]methyl}-N- [3-(1,1,2,2-tetrafluoroethoxy)benzyl]methanamine 681.24 1.26 244

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(4-ethoxyphenyl)-2-phenyl-1H-imidazol-5-yl]methyl}-N- (3-ethoxybenzyl)methanamine 617.33 1.26 245

* 1-(1,3-benzodioxol-5-yl)-N-({1- butyl-4-[4-(methylthio)phenyl]-2-phenyl-1H-imidazol-5-yl}methyl)-N- (3-ethoxybenzyl)methanamine 619.291.26 246

* 1-(1,3-benzodioxol-5-yl)-N-({1- butyl-4-[4-(ethylthio)phenyl]-2-phenyl-1H-imidazol-5-yl}methyl)-N- (3-ethoxybenzyl)methanamine 633.31.26 247

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-methoxyphenyl)-2-phenyl-1H-imidazol-5-yl]methyl}-N- (3-ethoxybenzyl)methanamine 603.311.23 248

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-ethoxyphenyl)-2-phenyl-1H-imidazol-5-yl]methyl}-N-(3- ethoxybenzyl)methanamine 617.33 1.26 249

* 1-(1,3-benzodioxol-5-yl)-N-({1- butyl-4-[3-(methylthio)phenyl]-2-phenyl-1H-imidazol-5-yl}methyl)-N- (3-ethoxybenzyl)methanamine 619.291.25 250

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-methylphenyl)-2-phenyl-1H-imidazol-5-yl]methyl}-N-(3- ethoxybenzyl)methanamine 587.31 1.25 251

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(4-methylphenyl)-2-phenyl-1H-imidazol-5-yl]methyl}-N-(3- ethoxybenzyl)methanamine 587.31 1.25 252

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3,4-dimethylphenyl)-2-phenyl-1H-imidazol-5-yl]methyl}-N- (3-ethoxybenzyl)methanamine 601.331.29 253

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3,5-dimethylphenyl)-2-phenyl-1H-imidazol-5-yl]methyl}-N- (3-ethoxybenzyl)methanamine 601.331.28 254

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-fluorophenyl)-2-phenyl-1H-imidazol-5-yl]methyl}-N-(3- ethoxybenzyl)methanamine 591.29 1.24 255

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(4-fluorophenyl)-2-phenyl-1H-imidazol-5-yl]methyl}-N-(3- ethoxybenzyl)methanamine 591.29 1.24 256

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3,4-difluorophenyl)-2-phenyl-1H-imidazol-5-yl]methyl}-N- (3-ethoxybenzyl)methanamine 609.281.26 257

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3,5-difluorophenyl)-2-phenyl-1H-imidazol-5-yl]methyl}-N- (3-ethoxybenzyl)methanamine 609.281.28 258

* 1-(1,3-benzodioxol-5-yl)-N-({1- butyl-2-phenyl-4-[3-(trifluoromethyl)phenyl]-1H- imidazol-5-yl}methyl)-N-(3-ethoxybenzyl)methanamine 641.29 1.27 259

* 1-(1,3-benzodioxol-5-yl)-N-({1- butyl-2-phenyl-4-[4-(trifluoromethyl)phenyl]-1H- imidazol-5-yl}methyl)-N-(3-ethoxybenzyl)methanamine 641.29 1.27 260

* 1-(1,3-benzodioxol-5-yl)-N-({1- butyl-2-phenyl-4-[4-(trifluoromethoxy)phenyl]-1H- imidazol-5-yl}methyl)-N-(3-ethoxybenzyl)methanamine 657.28 1.27 261

* 1-(1,3-benzodioxol-5-yl)-N-({1- butyl-2-phenyl-4-[4-(trifluoromethoxy)phenyl]-1H- imidazol-5-yl}methyl)-N-(3-ethoxybenzyl)methanamine 657.28 1.29 262

* 1-(1,3-benzodioxol-5-yl)-N-({1- butyl-4-[(1E)-pent-1-enyl]-2-phenyl-1H-imidazol-5-yl}methyl)-N- (3-ethoxybenzyl)methanamine 565.331.27 263

* 1-(1,3-benzodioxol-5-yl)-N-({1- butyl-2-phenyl-4-[3-(trifluoromethyl)phenyl]-1H- imidazol-5-yl}methyl)-N-[3-(1,1,2,2-tetrafluoroethoxy) benzyl]methanamine 264

* 1-(1,3-benzodioxol-5-yl)-N-({1- butyl-2-phenyl-4-[4-(trifluoromethyl)phenyl]-1H- imidazol-5-yl}methyl)-N-[3-(1,1,2,2-tetrafluoroethoxy) benzyl]methanamine 265

* 1-(1,3-benzodioxol-5-yl)-N-({1- butyl-2-phenyl-4-[3-(trifluoromethoxy)phenyl]-1H- imidazol-5-yl}methyl)-N-[3-(1,1,2,2-tetrafluoroethoxy) benzyl]methanamine 266

* 1-(1,3-benzodioxol-5-yl)-N-({1- butyl-2-phenyl-4-[4-(trifluoromethoxy)phenyl]-1H- imidazol-5-yl}methyl)-N-[3-(1,1,2,2-tetrafluoroethoxy) benzyl]methanamine 267

* 1-(1,3-benzodioxol-5-yl)-N-({1- butyl-4-[(1E)-pent-1-enyl]-2-phenyl]-1H-imidazol-5-yl}methyl)- N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]methanamine 637.29 1.25 268

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(4-chlorophenyl)-2-phenyl-1H-imidazol-5-yl]methyl)-N-(3- ethoxybenzyl)methanamine 607.26 1.27 269

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-chlorophenyl)-2-phenyl-1H-imidazol-5-yl]methyl}-N-(3- ethoxybenzyl)methanamine 607.26 1.27 270

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-isopropylphenyl)-2-phenyl-1H-imidazol-5-yl]methyl}- N-(3-ethoxybenzyl)methanamine 615.351.29 271

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(2,4-difluorophenyl)-2-phenyl-1H-imidazol-5-yl]methyl}- N-(3-ethoxybenzyl)methanamine 609.281.25 272

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(4-chlorophenyl)-2-phenyl-1H-imidazol-5-yl]methyl}-N-[3- (1,1,2,2-tetrafluoroethoxy)benzyl]methanamine 679.22 1.25 273

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-chlorophenyl)-2-phenyl-1H-imidazol-5-yl]methyl}-N-[3- (1,1,2,2-tetrafluoroethoxy)benzyl]methanamine 679.22 1.26 274

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(3-isopropylphenyl)-2-phenyl-1H-imidazol-5-yl]methyl}- N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]methanamine 687.31 1.26 275

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-(2,4-difluorophenyl)-2-phenyl-1H-imidazol-5-yl]methyl}- N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]methanamine 681.24 1.25 276

* 1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1-butyl-4-(3-isopropylphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}methanamine 615.31 1.27 277

* 1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1-butyl-4-(3,4-dimethylphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}methanamine 278

* 1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1-butyl-4-(2,4-difluorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}methanamine 609.24 1.23 279

* 1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1-butyl-4-(3,5-difluorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}methanamine 609.24 1.26 280

* 1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-({1-butyl-2-phenyl-4-[(E)-2- phenylethenyl]-1H-imidazol-5-yl}methyl)methanamine 599.28 1.23 281

* 1-(1,3-benzodioxol-5-yl)-N-({1- butyl-2-phenyl-4-[(E)-2-phenylethenyl]-1H-imidazol-5- yl}methyl)-N-(3- ethoxybenzyl)methanamine599.31 1.27 282

* 1-(1,3-benzodioxol-5-yl)-N-({1- butyl-2-phenyl-4-[(E)-2-phenylethenyl]-1H-imidazol-5- yl}methyl)-N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl] methanamine 283

* N-(1,3-benzodioxol-5-ylmethyl)-N- [(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]butan-1- amine 453.22 1.15 284

* 4-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl] amino}methyl)benzamide 530.21 1.26 285

* 4-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5- yl)methyl]amino}methyl) benzenesulfonamide 566.181.24 286

* methyl 4-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5- yl)methyl]amino}methyl)benzoate 545.21 1.37 287

* 1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(3- methoxybenzyl)methanamine 517.21 1.35 288

* 6-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}(cyclohexylmethyl) amino]methyl}-3,4-dihydroquinolin-2(1H)-one 552.31 1.37 289

* 6-[(butyl{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}amino)methyl]-3,4- dihydroquinolin-2(1H)-one 512.28 1.19 290

* 6-[((1,3-benzodioxol-5- ylmethyl){[1-butyl-2-phenyl-4-(trifluoromethyl)-1H-imidazol-5- yl]methyl}amino)methyl]-3,4-dihydroquinolin-2(1H)-one 590.25 1.3 291

* 6-({benzyl[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]amino}methyl)-3,4- dihydroquinolin-2(1H)-one 554.3 1.18 292

* 6-({butyl[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]amino}methyl)-3,4- dihydroquinolin-2(1H)-one 520.32 1.13 293

* 6-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]amino}methyl)-3,4- dihydroquinolin-2(1H)-one598.29 1.17 294

* 6-{[[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl](cyclohexylmethyl) amino]methyl}-3,4-dihydroquinolin-2(1H)-one 560.35 1.23 295

* 6-({[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl][4-(difluoromethoxy)benzyl]amino} methyl)-3,4-dihydroquinolin -2(1H)-one620.3 1.16 296

* 1-(1-butyl-2-phenyl-1H-imidazol-5- yl)-N,N-bis(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)methamine 525.26 1.18 297

* 1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]-N,N-bis(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)methanamine 298

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N,N-bis(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)methanamine 601.29 1.21 299

* 1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3- dihydro-1,4-benzodioxin-6-ylmethyl)methanamine 300

* 1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3- dihydro-1-benzofuran-5-ylmethyl)methanamine 529.21 1.28 301

* N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N,N-bis(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amine 559.22 1.28 302

* 1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2-phenyl-4-(trifluoromethyl)-1H-imidazol-5-yl]methyl]-N-(2,3- dihydro-1,4-benzodioxin-6-ylmethyl)methanamine 579.23 1.37 303

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-2-phenyl-4-(trifluoromethyl)-1H-imidazol-5-yl]methyl}-N-(2,3- dihydro-1,4-benzofuran-5-ylmethyl)methanamine 563.24 1.35 304

* 1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1-butyl-4-phenyl-2-(1H-pyrazol-1-yl)- 1H-imidazol-5-yl]methyl} methanamine305

* 4-[(butyl{[1-butyl-4-(5-methylthien- 2-yl)-2-phenyl-1H-imidazol-5-yl]methyl}amino)methyl]benzamide 514.28 1.17 306

* N-{[1-butyl-4-(5-methylthien-2-yl)- 2-phenyl-1H-imidazol-5-yl]methyl}-N-(3-ethoxybenzyl)butan-1-amine 515.3 1.25 307

* N-{[1-butyl-4-(5-methylthien-2-yl)- 2-phenyl-1H-imidazol-5-yl]methyl}-N-[3-(1,1,2,2-tetrafluoroethoxy) benzyl]butan-1-amine 587.26 1.26 308

* N-(1,3-benzodioxol-5-ylmethyl)-N- {[1-butyl-4-(5-methylthien-2-yl)-2-phenyl-1H-imidazol-5- yl]methyl}butan-1-amine 515.26 1.2 309

* 1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(4-butyl-5-phenyl-4H-1,2,4-triazol-3- yl)methyl]methanamine 498.23 1.23 310

* 1-(1,3-benzodioxol-5-yl)-N-[(4- butyl-5-phenyl-4H-1,2,4-triazol-3-yl)methyl]-N- (cyclohexylmethyl)methanamine 460.28 1.28 311

* N-(1,3-benzodioxol-5-ylmethyl)-N- [(4-butyl-5-phenyl-4H-1,2,4-triazol-3-yl)methyl]butan-1-amine 420.25 1.14 312

* N-(1,3-benzodioxol-5-ylmethyl)-N- [(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-2-morpholin-4- ylethanamine 313

* 1-(1,3-benzodioxol-5-yl)-N-(1,3- benzoxazol-2-ylmethyl)-N-[(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]methanamine 570.26 1.19 314

* 1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N-(tetrahydro-2H-pyran- 4-ylmethyl)methanamine 537.3 1.17 315

N-(1,3-benzodioxol-5-ylmethyl)-N- [(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-2-piperidin-1- ylethanamine 550.33 1.06 316

N~1~-(1,3-benzodioxol-5- ylmethyl)-N~1~-[(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]- N~2~,N~2~-diethylethane-1,2- diamine538.33 1.06 317

* N-(1,3-benzodioxol-5-ylmethyl)-N- [(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-2-thiomorpholin-4- ylethanamine 318

* 1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N-[(2S)-tetrahydrofuran- 2-ylmethyl]methanamine 523.28 1.18319

* 523.28 1.18 320

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-methylchroman-4-amine 451.26 1.19 321

* N,N-bis(1,3-benzodioxol-5- ylmethyl)-2-(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)acetamide 601.26 1.17 322

* N,N-bis(1,3-benzodioxol-5- ylmethyl)-2-(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)ethanamine 587.28 1.1 323

1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(4-butyl-1-methyl-3-phenyl-1H- pyrazol-5-yl)methyl]methanamine 511.25 1.34324

N-(1,3-benzodioxol-5-ylmethyl)-N- [(4-butyl-1-methyl-3-phenyl-1H-pyrazol-5-yl)methyl]butan-1-amine 511.25 1.34 325

1-(1,3-benzodioxol-5-yl)-N-[(4- butyl-1-methyl-3-phenyl-1H-pyrazol-5-yl)methyl]-N-(3- ethoxybenzyl)methanamine 433.27 1.18 326

1-(1,3-benzodioxol-5-yl)-N-benzyl- N-[(4-butyl-1-methyl-3-phenyl-1H-pyrazol-5-yl)methyl]methanamine 511.28 1.34 327

1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(4-butyl-1-methyl-5-phenyl-1H- pyrazol-3-yl)methyl]methanamine 467.26 1.38328

N-(1,3-benzodioxol-5-ylmethyl)-N- [(4-butyl-1-methyl-5-phenyl-1H-pyrazol-3-yl)methyl]butan-1-amine 433.27 1.16 329

* 1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N-(1,4- dioxaspiro[4.5]dec-8- ylmethyl)methanamine 330

* 4-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]amino}methyl) cyclohexanone 331

* 4-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]amino}methyl)-1- methylcyclohexanol 332

* 1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N-[(2-methyl-1,3- benzoxazol-5-yl)methyl] methanamine 333

* 1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N-methylethanamine 334

* 4-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]amino}methyl) cyclohexanol 335

* N-(1,3-benzodioxol-5-ylmethyl)-N- [(5-butyl-1,3-diphenyl-1H-pyrazol-4-yl)methyl]butan-1-amine 495.29 1.15 336

* 1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(5-butyl-1,3-diphenyl-1H-pyrazol-4- yl)methyl]methanamine 573.26 1.19 337

* 1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N-[(2-methyl-1,3- benzothiazol-5-yl)methyl] methanamine600.26 1.22 338

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[(1-ethyl-3,5-dimethyl-1H-pyrazol-4- yl)methyl]butan-1-amine 339

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl] butan-1-amine 340

* 1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2-phenyl-4-thien-3-yl-1H-imidazol-5-yl)methyl]-N-[3- (1,1,2,2-tetrafluoroethoxy)benzyl]methanamine 651.22 1.22 341

* methyl 2-amino-4-[(butyl{[1-butyl- 4-(3-methoxyphenyl)-2-phenyl-1H-imidazol-5-yl]methyl}amino) methyl]benzoate 554.33 1.2 342

* 1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)methanamine587.28 1.21 343

* 1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro-1- benzofuran-5- ylmethyl)methanamine 571.281.22 344

* 1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2-phenyl-4-thien-3-yl-1H-imidazol-5-yl)methyl]-N-(3- ethoxybenzyl)methanamine 579.26 1.23 345

* 1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1-butyl-2-(4-fluorophenyl)-4-phenyl- 1H-imidazol-5-yl]methyl} methanamine346

* 1-(1-butyl-2-phenyl-1H-imidazol- 5-yl)-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N- (2,3-dihydro-1-benzofuran-5-ylmethyl)methanamine 509.27 1.16 347

* 1-(1-butyl-2-phenyl-1H-imidazol- 5-yl)-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)methanamine 511.28 1.2 348

* 1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-N-(2,3-dihydro-1-benzofuran-5- ylmethyl)methanamine 577.26 1.36 349

* 1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)methanamine 579.27 1.4 350

* 1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1-butyl-2-(4-methylphenyl)-4-phenyl- 1H-imidazol-5- yl]methyl}methanamine587.28 1.24 351

* 1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1-butyl-2-(2-methylphenyl)-4-phenyl- 1H-imidazol-5- yl]methyl}methanamine587.28 1.23 352

* 1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1-butyl-2-(3-fluorophenyl)-4-phenyl- 1H-imidazol-5- yl]methyl}methanamine591.25 1.22 353

* N-(1,3-benzodioxol-5-ylmethyl)-N- [(1-butyl-4-fluoro-2-phenyl-1H-imidazol-5-yl)methyl]butan-1- amine 354

* 1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-4-fluoro-2-phenyl-1H-imidazol-5-yl)methyl]-N- (cyclohexylmethyl)methanamine 355

* 1-(1,3-benzodioxol-5-yl)-N-benzyl- N-[(1-butyl-4-fluoro-2-phenyl-1H-imidazol-5- yl)methyl]methanamine 356

* N-[(1-butyl-4-fluoro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(cyclohexymethyl)-N-(1H-indol-5- ylmethyl)amine 472.3 1.16 357

* 1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N- (cyclohexylmethyl)methanamine 535.32 1.26 358

* N-{[1-butyl-4-phenyl-2-(1H- pyrazol-1-yl)-1H-imidazol-5-yl]methyl}-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)amine 359

* 4-(2-{(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]amino}ethyl)phenol 559.28 1.18 360

* methyl 2-amino-4-[((1,3- benzodioxol-5-ylmethyl){[1-butyl-2-phenyl-4-(trifluoromethyl)-1H- imidazol-5-yl]methyl}amino)methyl]benzoate 594.25 1.34 361

* 7-[((1,3-benzodioxol-5- ylmethyl){[1-butyl-2-phenyl-4-(trifluoromethyl)-1H-imidazol-5- yl]methyl}amino)methyl] quinazolin-4-ol589.23 1.27 362

* methyl 4-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]amino}methyl)-2- nitrobenzoate 632.26 1.18 363

* 1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1-butyl-4-(4-fluorophenyl)-2-phenyl- 1H-imidazol-5- yl]methyl}methanamine591.25 1.22 364

* 7-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]amino}methyl) quinazolin-4-ol 597.27 1.15 365

* 7-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]amino}methyl) quinazolin-4-amine 596.29 1.08366

* 7-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]amino}methyl)-N,N- diethylquinazolin-4-amine367

* 7-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]amino}methyl)-N- ethylquinazolin-4-amine 624.321.1 368

* 1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N-[(4-ethoxyquinazolin- 7-yl)methyl]methanamine 625.31 1.22369

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-methylmethanamine 370

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(cyclohexylmethyl)butan-1-amine 371

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-1-cyclohexyl-N-methylethanamine 372

* N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)butan-1-amine 373

* N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(4-(difluoromethoxy)benzyl]butan-1- amine 374

* N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(3-ethoxybenzyl)butan-1-amine 375

* N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(3-methoxybenzyl)butan-1-amine 376

* 1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1-butyl-2-phenyl-4-(phenylsulfonyl)- 1H-imidazol-5- yl]methyl}methanamine637.22 1.31 377

* 1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-4-fluoro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(3- ethoxybenzyl)methanamine 515.26 1.29 378

* 1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(1-butyl-4-fluoro-2-phenyl-1H- imidazol-5- yl)methyl]methanamine 515.221.23 379

* 1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N-methylmethanamine 453.24 1.11 380

* N-(1,3-benzodioxol-5-ylmethyl)-N- [(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]ethanamine 467.26 1.12 381

* N-(1,3-benzodioxol-5-ylmethyl)-N- [(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]propan-1-amine 481.27 1.16 382

* N-(1,3-benzodioxol-5-ylmethyl)-N- [(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-3-ethoxypropan-1- amine 525.3 1.17 383

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N-(2,3- dihyrdro-1-benzofuran-5-ylmethyl)methanamine 585.3 1.22 384

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)methanamine 587.31 1.25 385

* 1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N- methylmethanamine 411.17 1.09 386

* N-(1,3-benzodioxol-5-ylmethyl)-N- [(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]ethanamine 425.19 1.09 387

* N-(1,3-benzodioxol-5-ylmethyl)-N- [(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]propan-1- amine 439.2 1.12 388

* N-(1,3-benzodioxol-5-ylmethyl)-N- [(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-3- ethoxypropan-1-amine 389

* N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)-N-(2,3-dihydro-1-benzofuran-5-ylmethyl)amine 390

* N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)-N-(3- ethoxybenzyl)amine 391

* 1-(1,3-benzodioxol-5-yl)-N-{[1- butyl-4-phenyl-2-(1H-pyrazol-1-yl)-1H-imidazol-5-yl]methyl}-N-(3- ethoxybenzyl)methanamine 392

* 1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-{[1-butyl-2-(2,6-dimethylphenyl)-4- phenyl-1H-imidazol-5-yl]methyl}methanamine 393

* N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro-1-benzofuran-5- ylmethyl)butan-1-amine 394

* N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(3-(difluoromethoxy)benzyl]butan-1- amine 395

* 1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(5-butyl-1-phenyl-1H-pyrazol-4- yl)methyl]methanamine 396

* 1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N-[(1,1- dioxidotetrahydro-2H-thiopyran-4-yl)methyl]methanamine 397

* N-[1-(1,3-benzodioxol-5-yl)ethyl]- N-[(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]butan-1- amine 398

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[1-(3-ethoxyphenyl)ethyl]butan-1-amine 399

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-{1-[4-(difluoromethoxy)phenyl]ethyl} butan-1-amine 400

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[1-(2,3-dihydro-1,4-benzodioxin-6- yl)ethyl]butan-1-amine 401

* 4-(1-{butyl[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]amino}ethyl)benzoic acid 402

* N-{[3-(benzyloxy)isoxazol-5- yl]methyl}-N-[(1-butyl-2,4-diphenyl-1H-imidazol-5-yl) methyl]butan-1-amine 403

* 1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-[(2- methyl-1,3-benzothiazol-5-yl)methyl]methanamine 404

* N-[(1-butyl-4-chloro-2-phenyl- 1H-imidazol-5-yl)methyl]-N-[(2-methyl-1,3-benzothiazol-5- yl)methyl]butan-1-amine 405

* 1-(1,3-benzodioxoJ-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(5-butyl-3-chloro-6-phenylpyridazin -4-yl)methyl]methanamine 406

* N-(1,3-benzodioxol-5-ylmethyl)-N- [(5-butyl-3-chloro-6-phenylpyridazin-4-yl)methyl]butan- 1-amine 407

* N-[1-(1,3benzodioxol-5-yl)ethyl]- N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]propan-1- amine 408

* N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-[1-(2,3-dihydro-1,4-benzodioxin-6- yl)ethyl]propan-1-amine 409

* 1-(1,3-benzodioxol-5-yl)-N-[(5- butyl-3-chloro-6-phenylpyridazin-4-yl)methyl]-N-(3- ethoxybenzyl)methanamine

TABLE II Ca²⁺ RT CMP # STRUCTURE Mob. IUPAC Name MASS (min.) 410

4-[((1,3-benzodioxol-5- ylmethyl){[1-butyl-4-(4-methoxyphenyl)-2-phenyl-1H- imidazol-5- yl]methyl}amino)methyl]-benzamide 411

1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)methyl]methanamine 412

* 4-({benzyl[(1-butyl-2,4- diphenyl- 1H-imidazol-5-yl)methyl]amino}methyl)- 2,6-dichlorophenol 570.25 1.21 413

* 4-({benzyl[(1-butyl-2,4- diphenyl-1H- imidazol-5-yl)methyl]-amino}methyl)-2- chlorophenol 536.30 1.18 414

* 4-({(1,3-benzodioxol-5- ylmethyl)[1-(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)ethyl]amino}methyl)-2,6-dimethylphenol 588.42 1.21 415

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(3,4-dichlorobenzyl)butan-1-amine 520.31 1.26 416

* (1R)-N-(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)- N-(cyclohexylmethyl)pentan- 1-amine 417

(1R)-N,N-bis(1,3-benzodioxol- 5-ylmethyl)-1-(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)pentan-1-amine 418

* 419

* 420

* (1R)-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(2,3- dihydro-1-benzofuran-6-ylmethyl)pentan-1-amine 421

* (1R)-N-(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)- N-(2,3-dihydro-1- benzofuran-6-ylmethyl)-pentan-1-amine 628.48 1.27 422

* 423

* 628.48 1.27 424

* 4-{[[(1R)-1-(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)pentyl](cyclohexylmethyl)- amino]methyl}-2,6- dimethylphenol 425

* 4-({(1,3-benzodioxol-5- ylmethyl)[(1R)-1-(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)pentyl]amino}methyl)-2,6- dimethylphenol630.50 1.26 426

* 427

* 630.50 1.26 428

(1R)-N-(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)- N-(cyclohexylmethyl)- ethanamine 429

(1R)-N,N-bis(1,3-benzodioxol- 5-ylmethyl)-1-(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)ethanamine 430

* (1S)-N,N-bis(1,3-benzodioxol- 5-ylmethyl)-1-(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)ethanamine 431

* (1R)-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(2,3- dihydro-1-benzofuran-6- ylmethyl)ethanamine432

(1R)-N-(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)- N-(2,3-dihydro-1- benzofuran-6-ylmethyl)ethanamine 433

* (1S)-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(2,3- dihydro-1-benzofuran-6- ylmethyl)ethanamine434

* 4-{[[(1R)-1-(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)ethyl](cyclohexylmethyl)- amino]methyl}- 2,6-dimethylphenol 435

* 4-{[[(1S)-1-(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)ethyl](cyclohexyl- methyl)amino]methyl}- 2,6-dimethylphenol 436

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(3-fluoro-4-methoxybenzyl)butan- 1-amine 500.31 1.19 437

* N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol- 5-yl)-N-(3-fluoro-4-methoxybenzyl)methanamine 534.30 1.21 438

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(4-methoxy-3-methylbenzyl)butan- 1-amine 496.34 1.18 439

* N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)-N-(4-methoxy-3-methylbenzyl)methanamine 530.32 1.24 440

N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(3- chloro-4-fluorobenzyl)butan-1-amine 504.27 1.24 441

N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol- 5-yl)-N-(3-chloro-4-fluorobenzyl)methanamine 538.26 1.25 442

methyl 4-({butyl[1-(1-butyl- 2-phenyl-1H-imidazol-5- yl)ethyl]amino}-methyl)benzoate 448.31 1.19 443

methyl 4-({benzyl[1-(1-butyl- 2-phenyl-1H-imidazol-5- yl)ethyl]amino}-methyl)benzoate 482.29 1.19 444

methyl 4-({butyl[1-(1-butyl- 2-phenyl-1H-imidazol-5- yl)pentyl]amino}-methyl)benzoate 490.35 1.23 445

* 5-({benzyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)- 2-methoxyphenol 532.36 1.18 446

* 4-({butyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)- 2-methoxyphenol 498.38 1.1 447

* 4-({benzyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)- 2-methoxyphenol 532.37 1.17 448

* 4-({[(1-butyl-2,4-diphenyl- 1H-imidazol-5- yl)methyl]amino}methyl)-benzene-1,2-diol 428.32 1 449

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N,N-bis(4-methoxybenzyl)methanamine 546.39 1.21 450

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N,N-bis(3,4-dihydroxybenzyl)methanamine 451

N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[2-fluoro-5-(trifluoro- methyl)benzyl]butan-1- amine 538.31 1.24 452

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N- (4-methoxy-3,5-dimethylbenzyl)butan- 1-amine 510.37 1.2 453

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(3,5-dichloro-4-methoxybenzyl)- butan-1-amine 550.28 1.26 454

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(3-chloro-4-methoxybenzyl)- butan-1-amine 516.31 1.21 455

* N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)-N-(4-methoxy-3,5-dimethylbenzyl)methanamine 544.36 1.25 456

* 4-({butyl[(1-butyl-3-phenyl- 1H-imidazol-5- yl)methyl]amino}methyl)-benzamide 419.31 1.08 457

* N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)-N-(3,5-dichloro-4- methoxybenzyl)methanamine 584.26 1.25 458

* N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)-N-(3-chloro-4-methoxybenzyl)methanamine 550.30 1.23 459

4-{[[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl](2,3-dihydro-1-benzofuran-5- ylmethyl)amino]methyl}- benzenesulfonamide607.39 1.12 460

N-(1,3-benzodioxol-5-ylmethyl)- N-[(1S)-1-(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)ethyl]butan-1-amine 510.39 1.21 461

N-[(1S)-1-(1-buytl-2,4- diphenyl-1H-imidazol-5- yl)-ethyl]-N-(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)butan-1-amine 524.41 1.2 462

* 4-({butyl[(1S)-1-(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)ethyl]amino}methyl)benzoic acid 510.39 1.19 463

N-(1,3-benzodioxol-5-ylmethyl)- N-[(1R)-1-(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)ethyl]butan-1- amine 510.40 1.21 464

N-[(1R)-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)ethyl]-N-(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)butan-1-amine 524.41 1.21 465

4-({butyl[(1R)-1-(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)ethyl]amino}methyl)benzoic acid 510.40 1.18 466

methyl 4-({butyl[(1S)-1- (1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)ethyl]-amino}methyl)benzoate 524.41 1.22 467

methyl 4-({butyl[(1R)-1- (1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)ethyl]-amino}methyl)benzoate 524.41 1.22 468

* 4-({butyl[(1S)-1-(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)ethyl]amino}methyl)- benzamide 509.42 1.15 469

4-({butyl[(1R)-1-(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)ethyl]amino}methyl)- benzamide 509.43 1.15 470

4-({butyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)-2,6- dichlorophenol 536.27 1.22 471

* 5-({butyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)-2- methoxyphenol 498.38 1.11 472

* 4-({benzyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)-2- methylphenol 516.37 1.21 473

* 4-({butyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)-2- methylphenol 482.38 1.12 474

* 4-({butyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)-2- chlorophenol 502.33 1.16 475

N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)-N-[2-fluoro-3-(trifluoromethyl)benzyl]- methanamine 572.32 1.24 476

N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[2-fluoro-3-(trifluoromethyl)- benzyl]butan-1- amine 539.36 1.25 477

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[2-fluoro-3-(trifluoromethyl)- benzyl]methanamine 578.38 1.29 478

* 1-(1,3-benzodioxol-5-yl)-N- [(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N- [2-fluoro-3- (trifluoromethyl)benzyl]-methanamine 616.32 1.22 479

N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)-N-[2-fluoro-4-(trifluoromethyl)benzyl]- methanamine 573.35 1.25 480

N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N- [2-fluoro-4-(trifluoromethyl)benzyl]butan- 1-amine 538.33 1.25 481

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[2-fluoro-4-(trifluoromethyl)- benzyl]methanamine 579.40 1.29 482

* 1-(1,3-benzodioxol-5-yl)-N- [(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N- [2-fluoro-4- (trifluoromethyl)benzyl]-methanamine 616.32 1.24 483

N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)-N-[2-fluoro-5-(trifluoromethyl)benzyl]- methanamine 573.35 1.24 484

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[2-fluoro-5-(trifluoromethyl)- benzyl]methanamine 579.40 1.28 485

* 1-(1,3-benzodioxol-5-yl)-N- [(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N- [2-fluoro-5- (trifluoromethyl)benzyl]-methanamine 617.35 1.23 486

* N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)-N-[4-(difluoromethoxy)- benzyl]methanamine 553.36 1.22 487

* N-[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)- benzyl]butan-1-amine 518.35 1.2 488

* 1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N- (cyclohexylmethyl)-N-[4-(difluoromethoxy)benzyl]- methanamine 559.41 1.26 489

* 1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N- [4-difluoromethoxy)benzyl]- methanamine 596.34 1.21 490

N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)- N-[3-fluoro-4-(trifluoromethyl)benzyl]- methanamine 572.32 1.24 491

* N-[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-N- [3-fluoro-4-(trifluoromethyl)benzyl]butan- 1-amine 538.33 1.25 492

1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N- (cyclohexylmethyl)-N-[3-fluoro-4- (trifluoromethyl)benzyl]- methanamine 579.40 1.28 493

* 1-(1,3-benzodioxol-5-yl)- N-[(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]- N-[3-fluoro-4- (trifluoromethyl)benzyl]-methanamine 616.32 1.23 494

* N-benzyl-1-(1-butyl-2,4- diphenyl- 1H-imidazol-5-yl)-N-[3-(trifluoromethyl)benzyl]- methanamine 552.29 1.22 495

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[3-(trifluoromethyl)benzyl]- butan-1-amine 518.30 1.2 496

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[3-(trifluoromethyl)benzyl]- methanamine 558.33 1.26 497

* 1-(1,3-benzodioxol-5-yl)-N- [(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N-[3- (trifluoromethyl)benzyl]- methanamine 596.281.21 498

* N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)-N-[4-(methylthio)- benzyl]methanamine 532.21 1.24 499

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4-(methylthio)benzyl]butan-1- amine 498.33 1.2 500

* N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)-N-[(2,2-dimethyl-3,4-dihydro-2H-chromen-6- yl)methyl]methanamine 570.39 1.27 501

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[(2,2-dimethyl-3,4-dihydro- 2H-chromen-6-yl)methyl]- butan-1-amine536.42 1.21 502

* N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol- 5-yl)-N-(4-iso-propylbenzyl)methanamine 528.37 1.28 503

* N-[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-N-(4-isopropylbenzyl)- butan-1-amine 494.38 1.24 504

* 2-{[1-(2,3-dihydro-1H-inden- 2-yl)-2-phenyl-1H- imidazol-5-yl]methyl}-1-(2-methylphenyl)-1,2,3,4- tetrahydroisoquinoline 496.30 1.24 505

* 1-(1,3-benzodioxol-5-yl)-N-[(1- butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]- N-[4-fluoro-3- (trifluoromethyl)benzyl]-methanamine 616.30 1.23 506

N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[3-fluoro-5-(trifluoro- methyl)benzyl]butan-1- amine 538.30 1.26 507

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[3-fluoro-5-(trifluoro- methyl)benzyl]- methanamine 578.34 1.28 508

* 1-(1,3-benzodioxol-5-yl)-N- [(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N- [3-fluoro-5- (trifluoromethyl)benzyl]-methanamine 616.29 1.24 509

N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol- 5-yl)-N-[4-fluoro-3-(trifluoromethyl)benzyl]- methanamine 588.28 1.26 510

N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N- [4-chloro-3-(tri-fluoromethyl)benzyl]butan- 1-amine 554.30 1.25 511

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4-chloro-3-(trifluoromethyl)benzyl]-N- (cyclohexylmethyl)- methanamine 594.33 1.3512

1-(1,3-benzodioxol-5-yl)-N- [(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N- [4-chloro-3- (trifluoromethyl)benzyl]-methanamine 632.28 1.24 513

N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N- [2-chloro-3-(trifluoromethyl)benzyl]butan- 1-amine 554.28 1.26 514

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- [2-chloro-3-(trifluoromethyl)benzyl]-N- (cyclohexylmethyl)- methanamine 594.32 1.3515

* 1-(1,3-benzodioxol-5-yl)-N- [(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N- [2-chloro-3- (trifluoromethyl)benzyl]-methanamine 632.27 1.24 516

N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol- 5-yl)-N-[2-chloro-5-(trifluoromethyl)benzyl]- methanamine 588.28 1.25 517

N-[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-N-[2-chloro-5-(trifluoro- methyl)benzyl]butan-1- amine 554.28 1.26 518

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- [2-chloro-5-(tri-fluoromethyl)benzyl]-N- (cyclohexylmethyl)- methanamine 594.34 1.29 519

1-(1,3-benzodioxol-5-yl)-N- [(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N- [2-chloro-5- (trifluoromethyl)benzyl]-methanamine 632.27 1.25 520

N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol- 5-yl)-N-[2,3-difluoro-4-(trifluoromethyl)benzyl]- methanamine 590.28 1.24 521

N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[2,3-difluoro-4-(tri- fluoromethyl)benzyl]butan- 1-amine 557.33 1.26 522

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[2,3-difluoro-4- (trifluoromethyl)benzyl]- methanamine 596.34 1.29 523

* 1-(1,3-benzodioxol-5-yl)-N- [(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N- [2,3-difluoro-4- (trifluoromethyl)benzyl]-methanamine 634.28 1.23 524

N-benzyl-1-[2,4-bis- (trifluoromethyl)phenyl]-N-[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl]methanamine 622.30 1.27525

N-[2,4-bis(trifluoro- methyl)benzyl]- N-[(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]butan-1- amine 589.34 1.28 526

1-[2,4-bis(trifluoro- methyl)phenyl]- N-[(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N- (cyclohexylmethyl)- methanamine 628.34 1.31527

N-benzyl-1-[2,5-bis- (trifluoromethyl)phenyl]-N-[(1-butyl-2,4-diphenyl-1H- imidazol-5- yl)methyl]methanamine 622.32 1.26528

* 1-(1,3-benzodioxol- 5-yl)-N-[2,5-bis- (trifluoromethyl)benzyl]-N-[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)- methyl]methanamine 666.311.25 529

N-[3,5-bis(trifluoro- methyl)benzyl]- N-[(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]butan-1- amine 588.32 1.27 530

1-[3,5-bis(trifluoro- methyl)phenyl]- N-[(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-N- (cyclohexylmethyl)- methanamine 628.39 1.32531

* 1-(1,3-benzodioxol-5-yl)- N-[3,5-bis(trifluoromethyl)-benzyl]-N-[(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)methyl]methanamine667.33 1.25 532

* 4-({benzyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)-2- methylphenyl acetate 558.35 1.22 533

* 4-({butyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)-2- methylphenyl acetate 524.37 1.19 534

* 4-({benzyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)- 2,6-dimethylphenyl acetate 572.37 1.23 535

* 4-({butyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)- 2,6-dimethylphenyl acetate 538.38 1.2 536

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[2-fluoro-4-(trifluoromethyl)benzyl]- N-(4-methoxybenzyl)- methanamine 602.35 1.25537

* N,N-dibenzyl-1-(1-butyl- 2,4-diphenyl-1H- imidazol-5- yl)methanamine486.35 1.23 538

4-({benzyl[(1-butyl-2,4- diphenyl-1H-imidazol- 5-yl)methyl]amino}-methyl)-2,6-dimethyl- phenyl methanesulfonate 608.37 1.21 539

* N-butyl-N-[(1-butyl-2,4- diphenyl-1H-imidazol- 5-yl)methyl]-butan-1-amine 418.37 1.12 540

4-({butyl[(1-butyl-2,4- diphenyl-1H-imidazol- 5-yl)methyl]amino}-methyl)-2,6-dimethyl- phenyl methanesulfonate 574.28 1.21 541

* 4-({[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)- methyl][4-(trifluoro-methyl)benzyl]amino}- methyl)-2,6-dimethylphenol 598.37 1.25 542

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4-(difluoromethyl)benzyl]-N- [4-(trifluoromethyl)benzyl]- methanamine620.34 1.23 543

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N- [3-(trifluoromethyl)benzyl]- methanamine620.28 1.22 544

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4-(trifluoromethoxy)benzyl]-N- [3-(trifluoromethyl)benzyl]- methanamine639.30 1.26 545

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N,N-bis[4-(difluoromethoxy)benzyl]- methanamine 618.28 1.2 546

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N- [4-(trifluoromethoxy)benzyl]- methanamine547

4-({[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-[3-(trifluoromethyl)benzyl]- amino}methyl)-3- chlorophenol 604.25 1.22548

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4-(di-fluoromethoxy)benzyl]- N-[2-fluoro-4-(trifluoro- methyl)benzyl]-mathanamine 638.26 1.23 549

N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)-N-(3,4-dimethoxy-benzyl)methanamine 546.32 1.19 550

* N-[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-N-(3,4-dimethoxybenzyl)- butan-1-amine 512.33 1.13 551

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-(3,4-dimethoxybenzyl)- methanamine 552.37 1.24 552

1-(1,3-benzodioxol-5-yl)- N-[(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]- N-(3,4-dimethoxybenzyl)- methanamine 590.311.18 553

* N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)-N-(3,4-dimethoxy-benzyl)methanamine 546.32 1.23 554

N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(3,5-dimethoxybenzyl)- butan-1-amine 512.32 1.2 555

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-(3,5-dimethoxybenzyl)- methanamine 552.36 1.27 556

* 1-(1,3-benzodioxol-5-yl)- N-[(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]- N-(3,5-dimethoxybenzyl)- methanamine 590.311.21 557

N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)-N-(3,4-diethoxybenzyl)- methanamine 574.35 1.23 558

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(3,4-diethoxybenzyl)- butan-1-amine 540.36 1.17 559

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-(3,4-diethoxybenzyl)- methanamine 581.42 1.28 560

* 1-(1,3-benzodioxol-5-yl)- N-[(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]- N-(3,4-diethoxybenzyl)- methanamine 561

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]- N-(3,4-dimethoxybenzyl)- methanamine 612.321.19 562

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(3,5-dimethoxybenzyl)-N-[3- (trifluoromethyl)benzyl]- methanamine 614.30 1.23563

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N- (3,5-dimethoxybenzyl)- methanamine 612.311.21 564

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(3,4-diethoxybenzyl)-N-[4- (difluoromethoxy)benzyl]- methanamine 640.34 1.22565

* 4-({[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl][3-(trifluoromethyl)benzyl]- amino}methyl)benzene- sulfonamide 633.27 1.15566

* 4-({[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl][4-(difluoromethoxy)benzyl]- amino}methyl)benzene- sulfonamide 567

* 4-({[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl][4-(trifluoromethoxy)benzyl]- amino}methyl)benzene- sulfonamide 649.27 1.16568

* (1R)-N-(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)-N-[4-(difluoromethoxy)-benzyl]pentan-1-amine 652.43 1.26 569

* (1R)-N-(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)-N-[4-(difluoromethoxy)- benzyl]ethanamine611.40 1.21 570

(1R)-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[4- (difluoromethoxy)benzyl]- ethanamine 572.411.26 571

* (1S)-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[4- (difluoromethoxy)benzyl]- pentan-1-amine 615.501.3 572

* (1S)-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[4- (difluoromethoxy)benzyl]- ethanamine 572.411.26 573

* 610.37 1.22 574

* 652.42 1.26 575

* N-[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-N-[2-chloro-4-(difluoro- methoxy)benzyl]butan- 1-amine 552.27 1.25 576

* N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)-N-[2-chloro-4-(difluoro- methoxy)benzyl]- methanamine 586.26 1.24 577

* 4-({[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-[2-chloro-4-(difluoro- methoxy)benzyl]- amino}methyl)benzene-sulfonamide 665.25 1.15 578

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)-3- methylbenzyl]butan-1- amine 533.35 1.21 579

* N-benzyl-3-butyl-N-[4- (difluoromethoxy)benzyl]-2-phenyl-3,4,5,6-tetra- hydrocyclopenta[d]- imidazol-4-amine 502.28 1.19580

N-benzyl-3-butyl-2-phenyl- N-[3-(trifluoromethyl)-benzyl]-3,4,5,6-tetra- hydrocyclopenta[d]- imidazol-4-amine 504.27 1.22581

* N,3-dibutyl-N-[4- (difluoromethoxy)benzyl]- 2-phenyl-3,4,5,6-tetra-hydrocyclopenta[d]- imidazol-4-amine 468.33 1.2 582

* N,3-dibutyl-2-phenyl-N- [3-(trifluoromethyl)benzyl]-3,4,5,6-tetrahydro- cyclopenta[d]imidazol-4- amine 470.30 1.23 583

* N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)-N-[4-(difluoromethoxy)- 3-methylbenzyl]- methanamine 566.31 1.24 584

* N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)-N-[4-(difluoromethoxy)- 3,5-dimethylbenzyl]- methanamine 580.37 1.25585

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)-3,5- dimethylbenzyl]butan- 1-amine 546.38 1.24 586

* N,1-dibutyl-5,5-dimethyl-2- phenyl-N-[3-(trifluoro-methyl)benzyl]-4,5,6,7- tetrahydro-1H- benzimidazol-7-amine 281.21 1.23587

* 1-butyl-N-[4- (difluoromethoxy)benzyl]- 5,5-dimethyl-2-phenyl-N-[3-(trifluoromethyl)benzyl]- 4,5,6,7-tetrahydro-1H- benzimidazol-7-amine281.21 1.23 588

* bis(1,3-benzodioxol-5-yl- methyl)(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl- amine oxide 590.29 1.22 589

* N-[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)-3- fluorobenzyl]butan-1- amine 590.29 1.23 590

* N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)-N-[4-(difluoromethoxy)- 3-fluorobenzyl]- methanamine 537.36 1.22 591

* 4-({[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl][4-(difluoromethoxy)-3- fluorobenzyl]amino}- methyl)benzenesulfonamide570.33 1.22 592

* 4-({[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl][4-(difluoromethoxy)-3,5- dimethylbenzyl]amino}- methyl)benzenesulfonamide649.33 1.13 593

* (1S)-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[3- (trifluoromethyl)benzyl]- pentan-1-amine 659.361.17 594

* (1R)-N-(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)- N-[3-(trifluoromethyl)-benzyl]pentan-1-amine 616.43 1.33 595

* (1R)-N-(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)- N-[3-(trifluoromethyl)- benzyl]ethanamine654.38 1.28 596

* (1R)-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[3- (trifluoromethyl)benzyl]- ethanamine 612.331.23 597

* (1R)-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[3- (trifluoromethyl)benzyl]- pentan-1-amine 574.371.28 598

* (1S)-1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[3- (trifluoromethyl)benzyl]- ethanamine 616.421.32 599

* (1S)-N-(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)- N-[3-(trifluoromethyl)- benzyl]ethanamine574.37 1.29 600

* (1S)-N-(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)- N-[3-(trifluoromethyl)-benzyl]pentan-1-amine 612.33 1.24 601

* N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)-N-(4-ethoxybenzyl)- methanamine 654.37 1.27 602

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(4-ethoxybenzyl)butan-1-amine 530.32 1.25 603

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-(4-ethoxybenzyl)methanamine 496.33 1.18 604

* 1-(1,3-benzodioxol-5-yl)- N-[(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N- (4-ethoxybenzyl)- methanamine 536.37 1.29 605

* N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)-N-(3-ethoxybenzyl)- methanamine 574.32 1.23 606

* N-[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-N-(3-ethoxybenzyl)- butan-1-amine 530.32 1.25 607

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-(3-ethoxybenzyl)methanamine 496.33 1.21 608

* 1-(1,3-benzodioxol-5-yl)- N-[(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N- (3-ethoxybenzyl)- methanamine 536.36 1.29 609

* N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol- 5-yl)-N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]- methanamine 574.32 1.23 610

* N-[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-N-[3-(1,1,2,2-tetrafluoro- ethoxy)benzyl]butan- 1-amine 602.29 1.22 611

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(cyclo-hexylmethyl)-N-[3-(1,1,2,2- tetrafluoroethoxy)benzyl]- methanamine568.30 1.23 612

* 1-(1,3-benzodioxol-5-yl)- N-[(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N- [3-(1,1,2,2-tetrafluoro- ethoxy)benzyl]-methanamine 608.33 1.27 613

* N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)-N-[3-(difluoromethoxy)- benzyl]methanamine 646.28 1.22 614

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[3-(difluoromethoxy)benzyl]- butan-1-amine 518.30 1.21 615

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(cyclo-hexylmethyl)-N-[3- (difluoromethoxy)benzyl]- methanamine 559.36 1.26 616

* 1-(1,3-benzodioxol-5-yl)- N-[(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N- [3-(difluoromethoxy)benzyl]- methanamine 596.291.21 617

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[3-(difluoromethoxy)benzyl]- N-[3-(trifluoromethyl)benzyl]- methanamine620.27 1.23 618

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[3-(difluoromethoxy)benzyl]- N-[4-(difluoromethoxy)- benzyl]methanamine618.28 1.21 619

* N-benzyl-1-(1-butyl-2,4- diphenyl-1H- imidazol-5-yl)-N-[2-(difluoromethoxy)benzyl]- methanamine 552.29 1.22 620

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[2-(difluoromethoxy)benzyl]- butan-1-amine 519.33 1.21 621

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[2-(difluoromethoxy)benzyl]- methanamine 559.37 1.26 622

* 1-(1,3-benzodioxol-5-yl)-N- [(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N-[2- (difluoromethoxy)benzyl]- methanamine 596.281.21 623

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[2-(difluoromethoxy)benzyl]- N-[3-(trifluoromethyl)- benzyl]methanamine620.28 1.23 624

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[2-(difluoromethoxy)benzyl]- N-[4-(difluoromethoxy)- benzyl]methanamine619.32 1.2 625

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[4-(difluoromethoxy)-3,5- dimethylbenzyl]- methanamine 586.37 1.3 626

* 1-(1,3-benzodioxol-5-yl)-N- [(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N- [4-(difluoromethoxy)-3,5- dimethylbenzyl]-methanamine 625.35 1.25 627

1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4- (difluoromethoxy)-3,5-dimethylbenzyl]-N-[3- (trifluoromethyl)benzyl]- methanamine 649.35 1.27628

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N- [4-(difluoromethoxy)-3,5- dimethylbenzyl]-methanamine 647.35 1.24 629

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-[4-(difluoromethoxy)-3- fluorobenzyl]methanamine 577.36 1.26 630

* 1-(1,3-benzodioxol-5-yl)-N- [(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N- [4-(difluoromethoxy)-3- fluorobenzyl]-methanamine 614.28 1.21 631

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4- (difluoromethoxy)-3-fluorobenzyl]-N-[3-(tri- fluoromethyl)benzyl]- methanamine 638.27 1.23632

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N- [4-(difluoromethyl)-3- fluorobenzyl]-methanamine 636.28 1.21 633

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4-(difluoromethoxy)-3-methyl- benzyl]-N-[3-(trifluoro- methyl)benzyl]-methanamine 634.29 1.25 634

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]- N-[4-(difluoromethoxy)-3- methylbenzyl]-methanamine 632.31 1.23 635

* 1-(1,3-benzodioxol-5-yl)- N-[(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N-(4- methoxy-3,5-dimethyl- benzyl)methanamine588.33 1.24 636

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(4- ethoxybenzyl)-N-[3-(trifluoromethyl)benzyl]- methanamine 598.32 1.26 637

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]- N-(4-ethoxy- benzyl)methanamine 596.32 1.23638

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(3- ethoxybenzyl)-N-[3-(trifluoromethyl)benzyl]- methanamine 599.34 1.26 639

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]- N-(3-ethoxy- benzyl)methanamine 596.31 1.23640

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-N- [3-(trifluoromethyl)- benzyl]methanamine670.27 1.24 641

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N- [3-(1,1,2,2-tetrafluoro- ethoxy)benzyl]-methanamine 668.28 1.22 642

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(4- methoxy-3-methyl-benzyl)-N-[3-(trifluoro- methyl)benzyl]- methanamine 598.31 1.27 643

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]- N-(4-methoxy-3- methylbenzyl)- methanamine596.32 1.24 644

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(2,3-dihydro-1-benzofuran-5- ylmethyl)-N-[3-(trifluoro- methyl)benzyl]-methanamine 596.30 1.24 645

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]- N-(2,3-dihydro-1- benzofuran-5-ylmethyl)-methanamine 594.31 1.22 646

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(4- methoxy-3,5-dimethyl-benzyl)-N-[3-(trifluoro- methyl)benzyl]- methanamine 613.36 1.27 647

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]- N-(4-methoxy-3,5- dimethylbenzyl)- methanamine611.37 1.24 648

* 1-(1,3-benzodioxol-5-yl)-N- (1,3-benzodioxol-5-ylmethyl)-N-{[1-butyl-2-phenyl-4-(tri- fluoromethyl)-1H-imidazol-5-yl]methyl}methanamine 566.28 1.36 649

* 1-butyl-N-[4-(difluoro- methoxy)benzyl]-N-[4- (difluoromethoxy)-3-fluorobenzyl]-5,5-dimethyl- 2-phenyl-4,5,6,7-tetra-hydro-1H-benzimidazol- 7-amine 281.23 1.21 650

* N-{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H- imidazol-5-yl]methyl}-N-[4-(difluoromethoxy)- benzyl]ethanamine 482.23 1.2 651

* methyl 4-({butyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]qmino}methyl)-2- methoxybenzoate 540.36 1.18 652

* methyl 4-{[[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl](cyclohexyl- methyl)amino]methyl}-2- methoxybenzoate 580.391.25 653

* methyl 4-({(1,3-benzodioxol- 5-ylmethyl)[(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]amino}methyl)- 2-methoxybenzoate619.37 1.18 654

* methyl 4-{[[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl](isopentyl)- amino]methyl}-2- methoxybenzoate 554.37 1.21 655

* 4-({butyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)- 2-methoxybenzamide 525.36 1.14 656

* 4-({butyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)- 2-hydroxybenzamide 511.34 1.16 657

* 4-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]amino}methyl)- 2-methoxybenzamide604.37 1.15 658

* 1-(1,3-benzodioxol-5-yl)- N-(1,3-benzodioxol-5-ylmethyl)-N-({1-butyl-4- [4-(ethylthio)phenyl]-2- phenyl-1H-imidazol-5-yl}methyl)methanamine 634.40 1.25 659

* 5-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}[4- (difluoromethoxy)benzyl]- amino}methyl)-1,3-benzoxazol-2(3H)-one 601.35 1.28 660

* 1-(1,3-benzodioxol-5-yl)-N- (1,3-benzodioxol-5- ylmethyl)-N-({1-butyl-4-[2-(methylthio)phenyl]- 2-phenyl-1H-imidazol-5- yl}methyl)methanamine620.39 1.22 661

* 1-(1,3-benzodioxol-5-yl)- N-(1,3-benzodioxol-5-ylmethyl)-N-({1-butyl-4-[(E)- 2-(4-fluorophenyl)- ethenyl]-2-phenyl-1H-imidazol-5-yl}- methyl)methanamine 618.41 1.23 662

* 1-(1,3-benzodioxol-5-yl)- N-(1,3-benzodioxol-5-ylmethyl)-N-({1-butyl-4- [3-(methylthio)phenyl]-2- phenyl-1H-imidazol-5-yl}methyl)methanamine 621.41 1.23 663

* 1-(1,3-benzodioxol-5-yl)- N-{[4-(1,3-benzodioxol-5-yl)-1-butyl-2-phenyl-1H- imidazol-5-yl]methyl}- N-(1,3-benzodioxol-5-ylmethyl}methanamine 619.42 1.21 664

* 1-(1,3-benzodioxol-5-yl)- N-(1,3-benzodioxol-5-ylmethyl)-N-{[1-butyl-4- (dimethoxymethyl)-2- phenyl-1H-imidazol-5-yl]methyl}methanamine 572.41 1.19 665

* 1-(1,3-benzodioxol-5-yl)- N-(1,3-benzodioxol-5-ylmethyl)-N-{[1-butyl-4- (difluoromethyl)-2- phenyl-1H-imidazol-5-yl]methyl}methanamine 548.34 1.28 666

* N,N-bis(1,3-benzodioxol-5- ylmethyl)-N-({1-butyl-4-[(methylamino)methyl]-2- phenyl-1H-imidazol-5- yl}methyl)amine 541.401.18 667

* (5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-2-phenyl-1H- imidazol-4-yl)methanol 528.36 1.17 668

* 1-(1,3-benzodioxol-5-yl)- N-(1,3-benzodioxol-5-ylmethyl)-N-{[1-butyl-4- (3-methoxyphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}methanamine 605.36 1.22 669

* 1-(1,3-benzodioxol-5-yl)- N-(1,3-benzodioxol-5-ylmethyl)-N-({1-butyl-2- phenyl-4-[4-(trifluoro- methoxy)phenyl]-1H-imidazol-5- yl}methyl)methanamine 658.31 1.24 670

* 1-(1,3-benzodioxol-5-yl)- N-(1,3-benzodioxol-5-ylmethyl)-N-{[1-butyl-4- (3,4-difluorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}methanamine 611.34 1.23 671

* 1-(1,3-benzodioxol-5-yl)- N-{[1-butyl-2-phenyl-4-(trifluoromethyl)-1H- imidazol-5-yl]methyl}-N- (3-ethoxybenzyl)-methanamine 566.31 1.4 672

* 1-(1,3-benzodioxol-5-yl)- N-{[1-butyl-2-phenyl-4-(trifluoromethyl)-1H- imidazol-5-yl]methyl}-N- [3-(1,1,2,2-tetrafluoro-ethoxy)benzyl]methanamine 639.31 1.36 673

* 1-(1,3-benzodioxol-5-yl)-N- (1,3-benzodioxol-5-ylmethyl)-N-{[1-butyl-4-(3- nitrophenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}methanamine 619.32 1.23 674

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(2,6-difluorobenzyl)-N-(4- methoxybenzyl)methanamine 552.33 1.23 675

* 4-({butyl[(1-butyl-2,4- diphenyl-1H- imidazol-5-yl)methyl]-amino}methyl)-2- hydroxybenzoic acid 512.34 1.21 676

* 4-{[[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-(cyclohexylmethyl)- amino]methyl}-2- methoxybenzoic acid 566.39 1.21 677

* 4-{[[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-(cyclohexylmethyl)amino]- methyl}-2-hydroxybenazmide 551.39 1.22 678

* 4-({benzyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)- 2-hydroxybenzamide 545.34 1.17 679

* 4-{[[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-(isopentyl)amino]methyl}- 2-methoxybenzamide 539.39 1.16 680

* 4-({benzyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)- 2-methoxybenzoic acid 560.34 1.17 681

* 4-{[[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-(isopentyl)amino]methyl}- 2-hydroxybenzamide 525.37 1.19 682

* 4-({benzyl[(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)methyl]amino}-methyl)-2- hydroxybenzoic acid 546.33 1.21 683

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(2-chloro-6-fluorobenzyl)-N-(4- methoxybenzyl)- methanamine 568.31 1.24 684

* 1-(1,3-benzodioxol-5-yl)- N-(1,3-benzodioxol-5-ylmethyl)-N-{[1-butyl-4- (4-methylphenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}methanamine 588.34 1.23 685

* 1-[1-butyl-2-(2-methoxy- phenyl)-4-(trifluoromethyl)-1H-imidazol-5-yl]-N,N- bis(3-ethoxybenzyl)- methanamine 596.34 1.42 686

* 1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H- imidazol-5-yl]-N,N-bis-(3-ethoxybenzyl)- methanamine 567.36 1.43 687

* 4-(5-{[bis(1,3-benzodioxol- 5-ylmethyl)amino]methyl}-1-butyl-2-phenyl-1H- imidazol-4- yl)benzonitrile 599.32 1.2 688

* 1-(1,3-benzodioxol-5-yl)- N-(1,3-benzodioxol-5-ylmethyl)-N-({1-butyl-2- phenyl-4-[4-(trifluoro- methyl)phenyl]-1H-imidazol-5- yl}methyl)methanamine 642.30 1.24 689

7-[(butyl{[1-butyl-4-(3- methoxyphenyl)-2-phenyl- 1H-imidazol-5-yl]-methyl}amino)methyl]- quinazolin-4-amine 690

1-(1,3-benzodioxol-5-yl)- N-[(1-butyl-4-chloro-2- phenyl-1H-imidazol-5-yl)methyl]-N-(3-ethoxy- benzyl)methanamine 691

* methyl 4-[(butyl{[1-butyl- 2-phenyl-4-(trifluoromethyl)-1H-imidazol-5-yl]methyl}- amino)methyl]-2- methoxybenzoate 532.31 1.3692

* 4-[(butyl{[1-butyl-2-phenyl- 4-(trifluoromethyl)-1H-imidazol-5-yl]methyl}- amino)methyl]-2- methoxybenzoic acid 518.30 1.26693

* 4-[(butyl{[1-butyl-2-phenyl- 4-(trifluoromethyl)-1H-imidazol-5-yl]methyl}- amino)methyl]-2- methoxybenzamide 517.32 1.25 694

* 4-[(butyl{[1-butyl-2-phenyl- 4-(trifluoromethyl)-1H-imidazol-5-yl]methyl}- amino)methyl]-2- hydroxybenzamide 503.30 1.25 695

* 1-(1,3-benzodioxol-5-yl)- N-[(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]- N-(1H-indol-5-yl- methyl)methanamine 569.361.2 696

* N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)-N-(1H-indol-5-yl-methyl)methanamine 525.36 1.21 697

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]- N-(1H-indol-5-yl-methyl)butan-1-amine 491.38 1.12 698

* 1-(1,3-benzodioxol-5-yl)- N-[(1-butyl-2-phenyl-1H-imidazol-5-yl)methyl]- N-[4-(difluoromethoxy)- benzyl]methanamine 520.261.18 699

* 5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-2-phenyl-1H- imidazole-4-carboxylic acid 542.27 1.09 700

* methyl 5-{[bis(1,3-benzodioxol- 5-ylmethyl)amino]methyl}-1-butyl-2-phenyl-1H- imidazole-4-carboxylate 556.27 1.21 701

* 1-(1-butyl-2-phenyl-1H- imidazol-5-yl)-N,N- bis(3-ethoxybenzyl)-methanamine 498.32 1.23 702

* 1-(1-butyl-2-phenyl-1H- imidazol-5-yl)-N-[3- (difluoromethoxy)-benzyl]-N-[4-(difluoro- methoxy)benzyl]- methanamine 542.26 1.18 703

* 2-(5-{[bis(1,3-benzodioxol- 5-ylmethyl)amino]-methyl}-1-butyl-2-phenyl- 1H-imidazol-4-yl)propan- 2-ol 556.32 1.15 704

* 1-(1,3-benzodioxol-5-yl)-N- [(4-bromo-1-butyl-2-phenyl-1H-imidazol-5-yl)methyl]- N-[4-(difluoromethoxy)- benzyl]methanamine598.19 1.32 705

* 1-[1-butyl-4-(4-methoxy- phenyl)-2-phenyl-1H- imidazol-5-yl]-N,N-bis(3-ethoxybenzyl)- methanamine 605.39 1.25 706

1-[1-butyl-4-(3-methoxy- phenyl)-2-phenyl-1H- imidazol-5-yl]-N,N-bis(3-ethoxybenzyl)- methanamine 707

* 1-(1,3-benzodioxol-5-yl)- N-(1,3-benzodioxol-5- ylmethyl)-N-[(1-butyl-4-ethoxy-2-phenyl-1H- imidazol-5-yl)- methyl]methanamine 257.18 1.18 708

* 1-[1-butyl-2-(3-methoxy- phenyl)-4-phenyl-1H- imidazol-5-yl]-N,N-bis-(3-ethoxybenzyl)- methanamine 604.36 1.26 709

* N-[(4-bromo-1-butyl-2- phenyl-1H-imidazol-5-yl)- methyl]-N,N-bis(3-ethoxybenzyl)amine 576.24 1.4 710

* N-[(4-bromo-1-butyl-2- phenyl-1H-imidazol-5- yl)methyl]-N,N-bis[4-(difluoromethoxy)- benzyl]amine 620.18 1.31 711

* N-[(1-butyl-4-chloro-2- phenyl-1H-imidazol-5-yl)- methyl]-N,N-bis(3-ethoxybenzyl)amine 532.29 1.4 712

* N-[(1-butyl-4-chloro-2- phenyl-1H-imidazol-5-yl)- methyl]-N,N-bis[4-(difluoromethoxy)- benzyl]amine 576.22 1.33 713

* 1-[1-butyl-4-(4-methoxy- phenyl)-2-phenyl-1H- imidazol-5-yl]-N-[4-(difluoromethoxy)benzyl]- N-(3-ethoxybenzyl)- methanamine 626.32 1.23714

* 1-(1,3-benzodioxol-5-yl)- N-{[1-butyl-4-(4-methoxy-phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}- N-[4-(difluoromethoxy)-benzyl]methanamine 626.30 1.21 715

* 1-[1-butyl-4-{4-methoxy- phenyl)-2-phenyl-1H-imidazol-5-yl]-N,N-bis[4- (difluoromethoxy)- benzyl]methanamine 648.301.2 716

* 1-[1-butyl-4-(3-methoxy- phenyl)-2-phenyl-1H- imidazol-5-yl)]-N-[4-(difluoromethoxy)benzyl]- N-(3-ethoxybenzyl)- methanamine 626.33 1.24717

* 1-(1,3-benzodioxol-5-yl)- N-{[1-butyl-4-(3-methoxy-phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}- N-[4-(difluoromethoxy)-benzyl]methanamine 626.30 1.21 718

* 1-[1-butyl-4-(3-methoxy- phenyl)-2-phenyl-1H-imidazol-5-yl]-N,N-bis[4- (difluoromethoxy)benzyl]- methanamine 648.301.21 719

* N-{[1-butyl-4-(3-ethoxy- phenyl)-2-phenyl-1H-imidazol-5-yl]methyl}-N-[4- (difluoromethoxy)benzyl]-N-(3-ethoxybenzyl)amine 640.34 1.26 720

* 1-(1,3-benzodioxol-5-yl)- N-{[1-butyl-4-(3-ethoxy-phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}- N-[4-(difluoromethoxy)-benzyl]methanamine 640.31 1.23 721

* N-{[1-butyl-4-(3-ethoxy- phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}-N,N-bis(3-ethoxybenzyl)- amine 619.40 1.28 722

* N-{[1-butyl-4-(3-ethoxy- phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}-N,N-bis[4- (difluoromethoxy)benzyl]- amine 662.31 1.23 723

* 1-(1-butyl-2-phenyl-4- thien-3-yl-1H-imidazol-5-yl)-N-[4-(difluoromethoxy)- benzyl]-N-(3-ethoxy- benzyl)methanamine602.28 1.22 724

* 1-(1,3-benzodioxol-5-yl)-N- [(1-butyl-2-phenyl-4-thien-3-yl-1H-imidazol-5- yl)methyl]-N-[4- (difluoromethoxy)-benzyl]methanamine 598.19 1.31 725

* 4-{[[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)- methyl](4-hydroxy-3,5-dimethylbenzyl)amino]- methyl}benzene- sulfonamide 609.35 1.12 726

* 4-{[[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)- methyl](4-hydroxy-3-methylbenzyl)amino]- methyl}benzene- sulfonamide 595.32 1.1 727

* 4-({[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)- methyl][4-(difluoromethoxy)-3- methylbenzyl]amino}- methyl)benzene- sulfonamide645.29 1.15 728

* N-benzyl-1-[3,4-bis- (difluoromethoxy)phenyl]-N-[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]- methanamine 618.281.21 729

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)- benzyl]propan-1-amine 504.30 1.18 730

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)- benzyl]pentan-1-amine 532.33 1.22 731

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)- benzyl]-cyclopentanamine 530.32 1.21 732

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)- benzyl]propan-2-amine 504.29 1.18 733

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)- benzyl]-2,2-dimethyl- propan-1-amine 533.35 1.24734

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)- benzyl]-3- methylbutan-1-amine 533.35 1.22 735

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)- benzyl]cyclohexanamine 544.33 1.23 736

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)- benzyl]ethanamine 490.28 1.16 737

* N-{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}-N-[4- (difluoromethoxy)benzyl]- pentan-1-amine 524.28 1.32738

* N-benzyl-1-[1-butyl-2-phenyl- 4-(trifluoromethyl)-1H-imidazol-5-yl]-N-[4- (difluoromethoxy)benzyl]- methanamine 544.24 1.37739

* N,1-dibutyl-N-[4- (difluoromethoxy)benzyl]-2-phenyl-4,5,6,7-tetrahydro- 1H-benzimidazol-7-amine 482.33 1.21 740

* N,1-dibutyl-N-(4-methoxy- 3,5-dimethylbenzyl)-2-phenyl-4,5,6,7-tetrahydro- 1H-benzimidazol-7-amine 474.37 1.26 741

* 4-{[butyl(1-butyl-2-phenyl- 4,5,6,7-tetrahydro-1H-benzimidazol-7-yl)amino]- methyl}-2,6- dimethylphenol 460.34 1.21 742

* N-{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H- imidazol-5-yl]methyl}-N-[4-(difluoromethoxy)- benzyl]butan-1-amine 510.27 1.28 743

* 4-[(butyl{[1-butyl-2-phenyl- 4-(trifluoromethyl)-1H-imidazol-5-yl]methyl}- amino)methyl]- benzenesulfonamide 523.27 1.23 744

* 1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H- imidazol-5-yl]-N-[4-(difluoromethoxy)benzyl]- N-(4-methoxy-3,5- dimethylbenzyl)- methanamine603.39 1.39 745

* 1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H- imidazol-5-yl]-N-[4-(difluoromethoxy)benzyl]- N-[4-(difluoromethoxy)- 3,5-dimethylbenzyl]-methanamine 639.38 1.37 746

* 1-(1,3-benzodioxol-5-yl)- N-{[1-butyl-2-phenyl-4-(trifluoromethyl)-1H- imidazol-5-yl]methyl}-N-[4-(difluoromethoxy)benzyl]- methanamine 588.30 1.34 747

* 1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H- imidazol-5-yl]-N-[4-(difluoromethoxy)benzyl]- N-[4-(difluoromethoxy)-3-fluorobenzyl]methanamine 628.29 1.32 748

* N-{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H- imidazol-5-yl]methyl}-N-(4-methoxy-3,5-dimethyl- benzyl)butan-1-amine 502.37 1.27 749

* 4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}[4- (difluoromethoxy)benzyl]- amino}methyl)-benzenesulfonamide 623.26 1.24 750

* 1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H- imidazol-5-yl]-N,N-bis[4-(difluoromethoxy)benzyl]- methanamine 610.26 1.33 751

* 5-({benzyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)- 2-(difluoromethoxy)phenol 568.28 1.21 752

* 5-({butyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)-2- (difluoromethoxy)phenol 534.30 1.17 753

* 4-{[[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-(4-methoxy-3,5-dimethyl- benzyl)amino]methyl}- benzenesulfonamide 623.331.16 754

* 4-{[[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-(2-chloro-4-hydroxybenzyl)- amino]methyl}benzene- sulfonamide 615.251.12 755

* 4-{[[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl](3-fluoro-4-methoxybenzyl)- amino]methyl}benzene- sulfonamide 613.29 1.12756

* 4-({[4-(aminosulfonyl)- benzyl][(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)- phenyl acetate 623.29 1.11 757

* 4-{[[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl](4-methoxybenzyl)amino]- methyl}phenyl acetate 574.31 1.2 758

* 2-(5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-2-phenyl-1H-imidazol- 4-yl)phenol 590.28 1.21 759

* 4-({butyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)-2- methylphenyl 3- methylbutanoate 567.40 1.26760

* 4-({benzyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)-2- methylphenyl 3- methylbutanoate 600.36 1.28761

* 2-(5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-4-phenyl-1H-imidazol- 2-yl)phenol 590.28 1.22 762

* 4-(5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-2-phenyl-1H-imidazol- 4-yl)phenol 590.27 1.2 763

* N-(1,3-benzodioxol-5- ylmethyl)-N-{[1-butyl-2-phenyl-4-(trifluoromethyl)- 1H-imidazol-5-yl]methyl}- butan-1-amine488.25 1.25 764

* N-{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}-N-[4-(difluoro- methoxy)-3-fluorobenzyl]- butan-1-amine528.24 1.34 765

* N-{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}-N-[4-(difluoro- methoxy)-3,5-dimethylbenzyl]- butan-1-amine538.28 1.32 766

* 4-[(benzyl{[1-butyl-2-phenyl- 4-(trifluoromethyl)-1H-imidazol-5-yl]methyl}- amino)methyl]- benzenesulfonamide 557.22 1.26 767

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(4- methoxybenzyl)-N-(4-methoxy-3,5-dimethyl- benzyl)methanamine 575.42 1.25 768

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-(4-methoxy-3,5-dimethyl- benzyl)methanamine 551.45 1.3 769

* 4-({benzyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)- 2-fluorophenol 520.32 1.19 770

* 4-({butyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)- 2-fluorophenol 486.34 1.15 771

* 4-{[[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-(3-fluoro-4-hydroxy- benzyl)amino] methyl}benzenesulfonamide 599.33 1.08772

* 4-{[[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-(4-methoxybenzyl)amino]- methyl}-2-fluorophenol 550.34 1.18 773

* 1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(cyclohex-3-en-1-ylmethyl)- N-(cyclohexylmethyl)- methanamine 496.391.32 774

* 4-{[[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-(cyclohexylmethyl)amino]- methyl}cyclohexane-1,2- diol 530.41 1.2 775

* 1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N- (cyclohexylmethyl)-N-(hexahydro-1,3-benzodioxol- 5-ylmethyl)methanamine 542.42 1.26 776

* 1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(cyclohex-3-en-1-ylmethyl)- N-[4-(difluoromethoxy)- benzyl]methanamine556.34 1.25 777

* 4-({[(1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl][4-(difluoromethoxy)benzyl]- amino}methyl)cyclohexane- 1,2-diol 590.36 1.15778

* 1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]- N-(hexahydro-1,3-benzo- dioxol-5-ylmethyl)-methanamine 602.35 1.19 779

* 1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[(2,2-difluoro-1,3-benzodioxol- 5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]-methanamine 632.31 1.24 780

* 1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[(2,2- difluoro-1,3-benzodioxol-5-yl)methyl]methanamine 573.38 1.29 781

N-[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-N-[(2,2-difluoro-1,3- benzodioxol-5-yl)methyl]- 3-methylbutan-1-amine546.33 1.26 782

* N-[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)benzyl]- hexan-1-amine 547.40 1.25 783

* N-[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-N-[(2,2-difluoro-1,3-benzo- dioxol-5-yl)methyl]- butan-1-amine 532.32 1.25784

* N-[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)benzyl]- heptan-1-amine 560.39 1.26 785

* N-[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)benzyl]- octan-1-amine 574.41 1.28 786

* N-[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)benzyl]- 3,3-dimethylbutan-1-amine 546.38 1.23 787

* N-[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-2-cyclohex-1-en-1-yl-N-[4- (difluoromethoxy)benzyl]- ethanamine 570.381.26 788

* 4-{[[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-(cyclohexylmethyl)amino]- methyl}-2-fluorophenol 526.37 1.24 789

* N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)-N-[(2,2-difluoro-1,3- benzodioxol-5-yl)- methyl]methanamine 566.32 1.24790

* 4-({[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl][(2,2-difluoro-1,3-benzodioxol-5- yl)methyl]amino}methyl)- benzenesulfonamide645.31 1.16 791

* 1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N-[(2,2-difluoro-1,3-benzodioxol-5- yl)methyl]-N-(4-methoxy- benzyl)methanamine596.33 1.25 792

* 4-({[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl][3-(1,1,2,2-tetrafluoroethoxy)- benzyl]amino}methyl)- benzenesulfonamide681.33 1.14 793

* 4-{[[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl](3-ethoxybenzyl)amino]methyl}- benzenesulfonamide 609.36 1.16 794

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(4- methoxybenzyl)-N-[3-(1,1,2,2-tetrafluoroethoxy)- benzyl]methanamine 632.35 1.23 795

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(3-ethoxy-benzyl)-N-(4-methoxy- benzyl)methanamine 560.37 1.25 796

* N-benzyl-1-[1-butyl-2- phenyl-4-(trifluoromethyl)-1H-imidazol-5-yl]-N-[4-(difluoro- methoxy)-3-fluoro- benzyl]methanamine562.27 1.36 797

* N-benzyl-1-[1-butyl-2- phenyl-4-(trifluoromethyl)-1H-imidazol-5-yl]-N-(4-methoxy- 3,5-dimethylbenzyl)- methanamine 536.321.43 798

* N,N-dibenzyl-1-[1-butyl- 2-phenyl-4-(trifluoro- methyl)-1H-imidazol-5-yl]methanamine 478.28 1.4 799

* 1-(1,3-benzodioxol-5-yl)-N- benzyl-N-{[1-butyl-2-phenyl-4-(trifluoromethyl)-1H- imidazol-5-yl]methyl}- methanamine 522.28 1.39800

* N-benzyl-1-[1-butyl-2-phenyl- 4-(trifluoromethyl)-1H-imidazol-5-yl]-N-[3-(1,1,2,2- tetrafluoroethoxy)benzyl]- methanamine594.28 1.37 801

* 4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}(4-hydroxy-3,5-dimethyl- benzyl}amino]methyl}-benzenesulfonamide 601.29 1.23 802

* 4-[(benzyl{[1-butyl-2-phenyl- 4-(trifluoromethyl)-1H-imidazol-5-yl]methyl}amino)- methyl]-2-fluorophenol 512.28 1.32 803

* 1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]-N-[4-(difluoro- methoxy)benzyl]-N-[3-(1,1,2,2-tetrafluoroethoxy)- benzyl]methanamine 660.28 1.34 804

* 1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]-N-[4-(difluoro- methoxy)benzyl]-N-(3-fluoro-4-methoxybenzyl)- methanamine 592.29 1.34 805

* 4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}[4- (difluoromethoxy)benzyl]- amino}methyl)-2-fluorophenol 578.29 1.29 806

* 4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}[4- (difluoromethoxy)-3-fluorobenzyl]amino}methyl)- benzenesulfonamide 641.24 1.23 807

* 4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}(2- chloro-4-hydroxybenzyl)- amino]methyl}-benzenesulfonamide 607.22 1.22 808

* 4-[((1,3-benzodioxol-5- ylmethyl){[1-butyl-2-phenyl-4-(trifluoromethyl)-1H- imidazol-5-yl]methyl]amino)-methyl]benzenesulfonamide 601.25 1.24 809

* 1-(1,3-benzodioxol-5-yl)-N- (1,3-benzodioxol-5-ylmethyl)-N-[(1-butyl-4-chloro-2- phenyl-1H-imidazol-5- yl)methyl]methanamine532.23 1.31 810

* N-benzyl-1-[1-butyl-2-phenyl- 4-(trifluoromethyl)-1H-imidazol-5-yl]-N-(3-fluoro-4- methoxybenzyl)methanamine 526.29 1.37 811

* 4-(5-{[bis(1,3-benzodioxol- 5-ylmethyl)amino]methyl}-1-butyl-4-phenyl-1H- imidazol-2-yl)phenol 590.32 1.2 812

* 4-({[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl][3-(difluoromethoxy)benzyl]- amino}methyl)- benzenesulfonamide 631.32 1.13813

* 4-{[[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl](3-methoxybenzyl)amino]- methyl}benzenesulfonamide 595.33 1.13 814

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[3-(difluoromethoxy)benzyl]- N-(4-methoxybenzyl)- methanamine 582.34 1.22815

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(3- methoxybenzyl)-N-(4-methoxybenzyl)- methanamine 546.35 1.22 816

* 1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]-N-[(2,2-difluoro-1,3- benzodioxol-5-yl)methyl]-N-[4-(difluoromethoxy)- benzyl]methanamine 624.25 1.36 817

* 4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}[(2,2-difluoro-1,3- benzodioxol-5-yl)methyl]-amino}methyl)benzene- sulfonamide 637.24 1.27 818

* 1-(1,3-benzodioxol-5-yl)- N-(1,3-benzodioxol-5-yl-methyl)-N-[(4-bromo-1- butyl-2-phenyl-1H- imidazol-5-yl)methyl]-methanamine 576.21 1.31 819

* 1-(1,3-benzodioxol-5-yl)- N-(1,3-benzodioxol-5-yl-methyl)-N-{[1-butyl-2- (2-methoxyphenyl)-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}- methanamine 596.27 1.35 820

* 1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H- imidazol-5-yl]-N-[4-(difluoromethoxy)benzyl]- N-(3-ethoxybenzyl)- methanamine 588.30 1.38821

* N-benzyl-1-[1-butyl-2-phenyl- 4-(trifluoromethyl)-1H-imidazol-5-yl]-N-(3- ethoxybenzyl)methanamine 522.30 1.41 822

* 4-({(1,3-benzodioxol-5- ylmethyl)[(1R)-1-(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)ethyl]amino}methyl)- benzenesulfonamide623.30 1.14 823

* 4-({(1,3-benzodioxol-5- ylmethyl)[(1S)-1-(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)ethyl]amino}methyl)- benzenesulfonamide623.30 1.13 824

* 4-{[[(1R)-1-(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)-ethyl](cyclohexylmethyl)- amino]methyl}- benzenesulfonamide 303.21 1.1825

* 4-({(1,3-benzodioxol-5- ylmethyl)[(1S)-1-(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)pentyl]amino}methyl)- benzenesulfonamide665.37 1.19 826

* N-(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2-phenyl-1H-imidazol-5-yl)- N-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]- pentan-1-amine 827

* N-(1,3-benzodioxol-5-yl- methyl)-1-(1-butyl-2-phenyl-1H-imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]- pentan-1-amine 576.321.22 828

* N-(1,3-benzodioxol-5-yl- methyl)-1-(1-butyl-2-phenyl-1H-imidazol-5-yl)-N-(3- ethoxybenzyl)- pentan-1-amine 554.34 1.25 829

* N,N-bis(1,3-benzodioxol-5- ylmethyl)-1-(1-butyl-2-phenyl-1H-imidazol-5-yl)pentan- 1-amine 554.31 1.23 830

* 4-({(1,3-benzodioxol-5- ylmethyl)[(1R)-1-(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)pentyl]amino}methyl)- benzenesulfonamide665.34 1.18 831

* methyl 4-[(butyl{[1-butyl-2- phenyl-4-(trifluoromethyl)-1H-imidazol-5-yl]methyl}amino)- methyl]benzoate 502.29 1.35 832

* 4-[{butyl{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}amino)methyl]- benzoic acid 488.27 1.28 833

* 4-[(butyl{[1-butyl-2-phenyl- 4-(trifluoromethyl)-1H-imidazol-5-yl]methyl}amino)- methyl]benzamide 487.32 1.25 834

* 4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}[3- (1,1,2,2-tetrafluoroethoxy)-benzyl]amino}methyl)- benzenesulfonamide 673.27 1.24 835

1-(1,3-benzodioxol-5-yl)- N-(1,3-benzodioxol-5-yl-methyl)-N-{[1-butyl-4- (diphenylphosphoryl)-2- phenyl-1H-imidazol-5-yl]methyl}methanamine 698.34 1.22 836

* 1-(1,3-benzodioxol-5-yl)- N-(1,3-benzodioxol-5-yl-methyl)-N-{[1-butyl-4- (2-methoxyphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}methanamine 604.34 1.22 837

* 1-(1,3-benzodioxol-5-yl)- N-{[1-butyl-2-(2-methoxy-phenyl)-4-(trifluoromethyl)- 1H-imidazol-5-yl]methyl)-N-[4-(difluoromethoxy)- benzyl]methanamine 619.32 1.35 838

* 4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}(3- ethoxybenzyl)amino] methyl}benzenesulfonamide601.25 1.27 839

* 4-[((1,3-benzodioxol-5- ylmethyl){[1-butyl-2-(2- methoxyphenyl)-4-(trifluoromethyl)-1H- imidazol-5-yl]methyl}amino)-methyl]benzenesulfonamide 631.22 1.24 840

* 4-[((1,3-benzodioxol-5- ylmethyl){[1-butyl-2-(2- methoxyphenyl)-4-(trifluoromethyl)-1H- imidazol-5-yl]methyl}- amino)methyl]-2,6-dimethylphenol 596.29 1.3 841

* 1-(1,3-benzodioxol-5-yl)-N- {[1-butyl-2-(2-methoxy-phenyl)-4-(trifluoromethyl)- 1H-imidazol-5-yl]methyl}-N-(3-ethoxybenzyl)- methanamine 842

* 1-(1,3-benzodioxol-5-yl)-N- {[1-butyl-2-(2-methoxy-phenyl)-4-(trifluoromethyl)- 1H-imidazol-5-yl]methyl}-N-[4-(difluoromethoxy)- 3-fluorobenzyl]- methanamine 637.26 1.34 843

* 1-(1,3-benzodioxol-5-yl)-N- {[1-butyl-2-(2-methoxy-phenyl)-4-(trifluoromethyl)- 1H-imidazol-5-yl]methyl}-N-[3-(difluoromethoxy)- benzyl]methanamine 619.27 1.34 844

* N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)-N-(2,3-difluorobenzyl)- methanamine 522.31 1.23 845

* N-[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-N-(2,3-difluorobenzyl)- butan-1-amine 488.32 1.25 846

* 1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N- (cyclohexylmethyl)-N-(2,3-difluorobenzyl)- methanamine 529.39 1.28 847

* 1-(1,3-benzodioxol-5-yl)- N-[(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]- N-(2,3-difluorobenzyl)- methanamine 567.341.21 848

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(2,3-difluorobenzyl)-N-[3- (trifluoromethyl)benzyl]- methanamine 591.34 1.23849

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-(2,3-difluorobenzyl)-N-[4- (difluoromethoxy)benzyl]- methanamine 588.31 1.24850

* N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol- 5-yl)-N-(3,5-di-fluorobenzyl)methanamine 522.32 1.24 851

* N-[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-N-(3,5-difluorobenzyl)- butan-1-amine 489.35 1.23 852

* 1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N- (cyclohexylmethyl)-N-(3,5-difluorobenzyl)- methanamine 528.37 1.29 853

* 1-(1,3-benzodioxol-5-yl)- N-[(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]- N-(3,5-difluorobenzyl)- methanamine 567.341.22 854

* 1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)- N-(3,5-difluorobenzyl)-N-[3-(trifluoromethyl)- benzyl]methanamine 590.30 1.24 855

* 1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)- N-(3,5-difluorobenzyl)-N-[4-(difluoromethoxy)- benzyl]methanamine 588.31 1.22 856

* 1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)- N-(3-chloro-4-fluorobenzyl)-N- (cyclohexylmethyl)- methanamine 544.35 1.29 857

* 1-(1,3-benzodioxol-5-yl)- N-[(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]- N-(3-chloro-4-fluoro- benzyl]methanamine582.29 1.23 858

* 1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)- N-(3-chloro-4-fluoro-benzyl)-N-[4-(difluoro- methoxy)benzyl]methanamine 604.29 1.23 859

* N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)-N-(4-chloro-3-fluoro- benzyl)methanamine 538.29 1.25 860

* N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]-N-(4-chloro-3-fluoro- benzyl)butan-1-amine 504.30 1.24 861

* 1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)- N-(4-chloro-3-fluoro-benzyl)-N-(cyclo- hexylmethyl)methanamine 544.35 1.29 862

* 1-(1,3-benzodioxol-5-yl)- N-[(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]- N-(4-chloro-3-fluoro- benzyl)methanamine582.29 1.24 863

* 1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)- N-(4-chloro-3-fluoro-benzyl)-N-[3-(trifluoro- methyl)benzyl]methanamine 606.28 1.25 864

* N-[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-N-(2-chloro-4-fluoro- benzyl)butan-1-amine 504.30 1.25 865

* 1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)- N-(2-chloro-4-fluoro-benzyl)-N-(cyclohexyl- methyl)methanamine 544.35 1.3 866

* 1-(1,3-benzodioxol-5-yl)-N- [(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N- (2-chloro-4-fluoro- benzyl)methanamine 582.291.24 867

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (2-chloro-4-fluoro-benzyl)-N-[3-(trifluoro- methyl)benzyl]- methanamine 606.28 1.25 868

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N- (2-chloro-4-fluoro-benzyl)-N-[4-(difluoro- methoxy)benzyl]- methanamine 604.28 1.24 869

* N-benzyl-1-(3-bromo-4- fluorophenyl)-N-[(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)methyl]methanamine 582.26 1.24 870

* N-(3-bromo-4-fluorobenzyl)- N-[(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]- butan-1-amine 548.26 1.25 871

* 1-(3-bromo-4-fluorophenyl)- N-[(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N- (cyclohexylmethyl)- methanamine 588.30 1.3 872

* 1-(1,3-benzodioxol-5-yl)- N-(3-bromo-4-fluorobenzyl)-N-[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]- methanamine 626.251.23 873

* 1-(3-bromo-4-fluorophenyl)- N-[(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N- [4-(difluoromethoxy)benzyl]- methanamine 648.251.23 874

* 3-(5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-2-phenyl-1H-imidazol- 4-yl)phenol 590.27 1.2 875

* 3-(5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-4-phenyl-1H-imidazol- 2-yl)phenol 590.27 1.21 876

* 4-[((1,3-benzodioxol-5- ylmethyl){[1-butyl-2-(2-methoxyphenyl)-4-(tri- fluoromethyl)-1H-imidazol-5-yl]methyl}amino)methyl]- 3-chlorophenol 602.20 1.32 877

* 1-(1,3-benzodioxol-5-yl)- N-(1,3-benzodioxol-5-yl-methyl)-N-[(1-butyl-2- phenyl-4-thien-3-yl-1H- imidazol-5-yl)methyl]methanamine 580.22 1.2 878

* methyl 4-{[{[1-butyl-2-phenyl- 4-(trifluoromethyl)-1H-imidazol-5-yl]methyl}- (isopentyl)amino]methyl}- benzoate 516.28 1.36879

* methyl 4-{[{[1-butyl-2-phenyl- 4-(trifluoromethyl)-1H-imidazol-5-yl]methyl}- (isobutyl)amino]methyl}- benzoate 502.26 1.37 880

methyl 4-{[{[1-butyl-2-phenyl- 4-(trifluoromethyl)-1H-imidazol-5-yl]methyl}- (cyclohexylmethyl)amino]- methyl}benzoate 542.301.45 881

* 4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H- imidazol-5-yl]methyl}-(isopentyl)amino]methyl}- benzoic acid 502.26 1.3 882

* 4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H- imidazol-5-yl]methyl}-(isobutyl)amino]methyl}- benzoic acid 488.25 1.32 883

* 4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H- imidazol-5-yl]methyl}-(cyclohexylmethyl)amino]- methyl}benzoic acid 528.28 1.39 884

* 4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H- imidazol-5-yl]methyl}-(cyclohexylmethyl)amino]- methyl}benzamide 527.30 1.34 885

* 4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H- imidazol-5-yl]methyl}-(isobutyl)amino]- methyl}benzamide 487.27 1.28 886

* 4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H- imidazol-5-yl]methyl}-(isopentyl)amino]- methyl}benzamide 501.29 1.25 887

* 1-(1,3-benzodioxol-5-yl)- N-(1,3-benzodioxol-5-yl-methyl)-N-{[1-butyl-4- (pentafluoroethyl)-2- phenyl-1H-imidazol-5-yl]methyl}methanamine 616.34 1.4 888

* 1-(1,3-benzodioxol-5-yl)- N-{[1-butyl-4-(penta- fluoroethyl)-2-phenyl-1H-imidazol-5-yl]- methyl}-N-[3-(1,1,2,2- tetrafluoroethoxy)benzyl]-methanamine 688.36 1.38 889

* 1-(1,3-benzodioxol-5-yl)- N-{[1-butyl-4-(penta- fluoroethyl)-2-phenyl-1H-imidazol-5-yl]- methyl}-N-[4- (difluoromethoxy)benzyl]- methanamine638.35 1.37 890

* 1-(1,3-benzodioxol-5-yl)- N-{[1-butyl-4-(penta- fluoroethyl)-2-phenyl-1H-imidazol-5-yl]- methyl}-N-(3- ethoxybenzyl}- methanamine 616.38 1.44891

* 1-(1,3-benzodioxol-5-yl)- N-{[1-butyl-4-(penta- fluoroethyl)-2-phenyl-1H-imidazol-5-yl]- methyl}-N-[3- (difluoromethoxy)benzyl]- methanamine638.34 1.37 892

* methyl 4-({{[1-butyl-2- phenyl-4-(trifluoromethyl)-1H-imidazol-5-yl]methyl}- [3-(difluoromethoxy)- benzyl]amino}methyl)-benzoate 602.35 1.33 893

* 1-(1-butyl-2-phenyl-1H- imidazol-5-yl)-N-[4-(di-fluoromethoxy)benzyl]- N-(3-ethoxybenzyl)- methanamine 520.26 1.21 894

* 1-[4-({benzyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)- phenyl]ethanone 528.29 1.19 895

* 1-[4-({butyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)- phenyl]ethanone 494.31 1.18 896

* 1-[4-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)methyl]amino}methyl)- phenyl]ethanone 572.291.18 897

* 1-[4-({[(1-butyl-2,4- diphenyl-1H-imidazol- 5-yl)methyl][4-(difluoro-methoxy)benzyl]amino}- methyl)phenyl]ethanone 594.29 1.18 898

* N-[4-({benzyl[(1-butyl- 2,4-diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)- phenyl]acteamide 543.31 1.17 899

* N-[4-({butyl[(1-butyl- 2,4-diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)- phenyl]acteamide 509.33 1.13 900

* N-[4-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]amino}methyl)- phenyl]acetamide 587.311.17 901

* N-[4-({[(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)methyl][4-(difluoromethoxy)benzyl]- amino}methyl)phenyl]- acetamide 609.31 1.18902

* N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)-N-[(6-methylpyridin-2- yl)methyl]methanamine 501.30 1.1 903

* N-[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)methyl]-N-[(6-methylpyridin-2- yl)methyl]butan-1-amine 467.31 1.09 904

* 1-(1,3-benzodioxol-5-yl)-N- [(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]-N- [(6-methylpyridin-2-yl)- methyl]methanamine545.30 1.09 905

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]- N-[(6-methylpyridin-2- yl)methyl]methanamine567.37 1.1 906

* N-[(4-bromo-1-butyl-2- phenyl-1H-imidazol-5-yl)-methyl]-N-[4-(difluoro- methoxy)benzyl]-N-(3- ethoxybenzyl)amine 598.271.36 907

* 1-(1,3-benzodioxol-5-yl)-N- (1,3-benzodioxol-5-ylmethyl)-N-({1-butyl-4-[4-(methylthio)- phenyl]-2-phenyl-1H-imidazol-5-yl}methyl)methanamine 620.32 1.24 908

* 1-(1,3-benzodioxol-5-yl)-N- (1,3-benzodioxol-5-ylmethyl)-N-({1-butyl-4-[4-(methyl- sulfonyl)phenyl]-2-phenyl-1H-imidazol-5-yl}methyl)- methanamine 652.32 1.19 909

* 1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]-N-[4-(difluoromethoxy)- benzyl]-N-[4-(methylthio)-benzyl]methanamine 590.27 1.38 910

* 4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}[4-(methylthio)- benzyl]amino}methyl) benzenesulfonamide603.27 1.27 911

* 1-(1,3-benzodioxol-5-yl)-N- {[1-butyl-2-(2-methoxyphenyl)-4-(trifluoromethyl)-1H- imidazol-5-yl]methyl}-N- [4-(methylthio)benzyl]-methanamine 598.28 1.4 912

1-[1-butyl-2-(2-methoxy- phenyl)-4-(trifluoromethyl)-1H-imidazol-5-yl]-N-[4- (difluoromethoxy)benzyl]-N-[4-(methylthio)benzyl]- methanamine 621.33 1.37 913

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[3-(di-fluoromethoxy)benzyl]- N-[4-(methylthio)benzyl]- methanamine 599.35 1.23914

1-(1,3-benzodioxol-5-yl)-N- {[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}-N- [4-(methylsulfonyl)benzyl]- methanamine 600.271.26 915

* methyl 4-({{[1-butyl-2-phenyl- 4-(trifluoromethyl)-1H-imidazol-5-yl]methyl}[4- (difluoromethoxy)benzyl]- amino}methyl)benzoate603.32 1.34 916

* methyl 4-[((1,3-benzodioxol-5- ylmethyl){[1-butyl-2-phenyl-4-(trifluoromethyl)-1H-imidazol- 5-yl]methyl}amino)methyl]- benzoate581.32 1.36 917

* 4-[((1,3-benzodioxol-5- ylmethyl){[1-butyl-2-phenyl-4-(trifluoromethyl)-1H- imidazol-5-yl]methyl}amino)- methyl]benzoic acid566.29 1.31 918

* 4-({{[1-butyl-2-phenyl- 4-(trifluoromethyl)-1H-imidazol-5-yl]methyl}[4- (difluoromethoxy)benzyl]- amino}methyl)benzoicacid 588.28 1.29 919

* 4-({{[1-butyl-2-phenyl- 4-(trifluoromethyl)-1H-imidazol-5-yl]methyl}[4- (difluoromethoxy)benzyl]-amino}methyl)benzamide 587.29 1.26 920

* 4-[((1,3-benzodioxol-5-yl- methyl){[1-butyl-2-phenyl-4-(trifluoromethyl)-1H- imidazol-5-yl]methyl}- amino)methyl]benzamide565.29 1.27 921

* methyl 4-({{[1-butyl-2- phenyl-4-(trifluoromethyl)-1H-imidazol-5-yl]methyl}[3- (1,1,2,2-tetrafluoroethoxy)-benzyl]amino}methyl)- benzoate 652.37 1.33 922

* methyl 4-{[{[1-butyl-2- phenyl-4-(trifluoromethyl)-1H-imidazol-5-yl]methyl}(3- ethoxybenzyl)amino]methyl}- benzoate 580.391.39 923

* 4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}[3- (difluoromethoxy)benzyl]- amino}methyl)benzoicacid 588.35 1.28 924

* 4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}[3- (1,1,2,2-tetrafluoro- ethoxy)benzyl]-amino}methyl)benzoic acid 638.36 1.3 925

* 4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}[3- ethoxybenzyl)amino]- methyl}benzoic acid 566.381.34 926

* 4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}[3- (trifluoromethyl)benzyl]- amino}methyl)benzoicacid 590.35 1.32 927

* 4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}[3- (difluoromethoxy)benzyl]-amino}methyl)benzamide 587.37 1.26 928

* 4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}(3- ethoxybenzyl)amino]- methyl}benzamide 565.391.3 929

* 4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}[3- (1,1,2,2-tetrafluoro- ethoxy)benzyl]-amino}methyl)benzamide 637.38 1.27 930

* 4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}[3- (trifluoromethyl)benzyl]-amino}methyl)benzamide 589.36 1.29 931

* 5-{[bis-(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-2-phenyl-1H- imidazole-4-carbonitrile 523.33 1.3 932

* 1-(1,3-benzodioxol-5-yl)-N- (1,3-benzodioxol-5-ylmethyl)-N-[(1-butyl-2-phenyl-4- pyrazin-2-yl-1H-imidazol-5-yl)methyl]methanamine 576.27 1.15 933

* 1-(1,3-benzodioxol-5-yl)-N- (1,3-benzodioxol-5-ylmethyl)-N-{[1-butyl-2-phenyl-4- (1,3-thiazol-2-yl)-1H- imidazol-5-yl]methyl}-methanamine 581.23 1.15 934

* 1-(1,3-benzodioxol-5-yl)-N- (1,3-benzodioxol-5-ylmethyl)-N-{[1-butyl-2-phenyl-4- (phenylethynyl)-1H- imidazol-5-yl]methyl}methanamine 598.28 1.28 935

* 1-(1,3-benzodioxol-5-yl)-N- (1,3-benzodioxol-5-ylmethyl)-N-({1-butyl-4-[(1E)-pent-1- enyl]-2-phenyl-1H-imidazol-5-yl}methyl)methanamine 566.31 1.23 936

* 566.31 1.24 937

* 1-(1,3-benzodioxol-5-yl)-N- (1,3-benzodioxol-5-ylmethyl)-N-[(1-butyl-2-phenyl-4-vinyl- 1H-imidazol-5-yl)- methyl]methanamine524.25 1.19 938

* 1-(1,3-benzodioxol-5-yl)-N- (1,3-benzodioxol-5-ylmethyl)-N-[(1-butyl-2-phenyl-4- pyridin-2-yl-1H-imidazol-5-yl)methyl]methanamine 575.28 1.15 939

* 1-[4-({{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}[4-(difluoro- methoxy)benzyl]amino}- methyl}phenyl]ethanone587.27 1.3 940

* 1-{4-[((1,3-benzodioxol-5- ylmethyl){[1-butyl-2-phenyl-4-(trifluoromethyl)-1H- imidazol-5-yl]methyl}- amino)methyl]phenyl}-ethanone 564.24 1.32 941

* 4-[((4-acetylbenzyl){[1-butyl- 2-phenyl-4-(trifluoromethyl)-1H-imidazol-5-yl]methyl}- amino)methyl]benzene- sulfonamide 599.23 1.2942

* N,N-bis(1,3-benzodioxol-5- ylmethyl)-1-[1-butyl-2-phenyl-4-(trifluoromethyl)-1H- imidazol-5-yl]ethanamine 580.27 1.37 943

* 1-(1,3-benzodioxol-5-yl)-N- (1,3-benzodioxol-5-ylmethyl)-N-{[1-butyl-4-(1-naphthyl)-2- phenyl-1H-imidazol-5-yl]methyl}methanamine 624.31 1.24 944

* 1-(1,3-benzodioxol-5-yl)-N- (1,3-benzodioxol-5-ylmethyl)-N-[(1-butyl-2-phenyl-4- pyridin-3-yl-1H-imidazol-5-yl)methyl]methanamine 575.29 1.21 945

* 1-(1,3-benzodioxol-5-yl)-N- (1,3-benzodioxol-5-ylmethyl)-N-{[1-butyl-4-(3-ethoxy- phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}-methanamine 618.30 1.24 946

* 1-(1,3-benzodioxol-5-yl)-N- (1,3-benzodioxol-5-ylmethyl)-N-{[1-butyl-4-(5-methyl- thien-2-yl)-2-phenyl-1H- imidazol-5-yl]methyl}-methanamine 595.29 1.24 947

* 1-(1,3-benzodioxol-5-yl)-N- (1,3-benzodioxol-5-ylmethyl)-N-({1-butyl-2-phenyl-4-[2- (trifluoromethyl)phenyl]-1H- imidazol-5-yl}-methyl)methanamine 643.32 1.25 948

* 5-({(1,3-benzodioxol-5-yl- methyl)[4-(difluoromethoxy)-benzyl]amino}methyl)-1- butyl-2-phenyl-1H- imidazole-4-carbonitrile545.25 1.3 949

* 4-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-4-cyano-2-phenyl-1H-imidazol-5- yl)methyl]amino}methyl)- benzenesulfonamide558.25 1.22 950

* 4-({(1,3-benzodioxol-5- ylmethyl)[(1-butyl-4-cyano-2-phenyl-1H-imidazol-5- yl)methyl]amino}methyl)- benzamide 522.27 1.22951

* 5-{[(1,3-benzodioxol-5-yl- methyl)(3-ethoxybenzyl)-amino]methyl}-1-butyl-2- phenyl-1H-imidazol-4- carbonitrile 523.29 1.34952

* 5-({(1,3-benzodioxol-5-yl- methyl)[3-(1,1,2,2-tetra-fluoroethoxy)benzyl]- amino}methyl)-1-butyl- 2-phenyl-1H-imidazole-4-carbonitrile 596.29 1.3 953

* 5-({(1,3-benzodioxol-5- ylmethyl)[3-(difluoro- methoxy)benzyl]amino}-methyl)-1-butyl-2-phenyl- 1H-imidazole-4- carbonitrile 546.28 1.29 954

* 1-(1,3-benzodioxol-5-yl)-N- (1,3-benzodioxol-5-ylmethyl}-N-[(1-butyl-4-methyl-2- phenyl-1H-imidazol-5- yl)methyl]methanamine512.27 1.19 955

* 1-(1,3-benzodioxol-5-yl)-N- (1,3-benzodioxol-5-ylmethyl)-N-[(1-butyl-4-ethyl-2-phenyl- 1H-imidazol-5-yl)- methyl]methanamine526.30 1.2 956

* N-[(1-butyl-4-chloro-2-phenyl- 1H-imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)- benzyl]-N-(3-ethoxy- benzyl)amine 554.28 1.36957

611.25 1.22 958

* 5-({butyl[(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-methyl]amino}methyl)-2- (methylamino)benzenethiol 512.33 1.23 959

* 5-({benzyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)- 2-(methylamino)- benzenethiol 546.33 1.26 960

* 1-(1,3-benzodioxol-5-yl)-N- (1,3-benzodioxol-5-ylmethyl)-N-{[1-butyl-4-(4-ethoxy- phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}-methanamine 618.35 1.23 961

* ethyl (2E)-3-(5-{[bis(1,3- benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-2-phenyl-1H- imidazol-4-yl)prop- 2-enoate 596.31 1.23 962

* 1-(1,3-benzodioxol-5-yl)-N- (1,3-benzodioxol-5-ylmethyl)-N-[(1-butyl-2-phenyl-4-thien- 2-yl-1H-imidazol-5-yl)- methyl]methanamine580.28 1.22 963

* 1-[5-(5-{[biS(1,3-benzodioxol- 5-ylmethyl)amino]methyl}-1-butyl-2-phenyl-1H-imidazol- 4-yl)thien-2-yl]ethanone 622.28 1.25 964

* 6-({butyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)- 3-methyl-1,3-benzothiazol- 2(3H)-one 539.331.18 965

* 1-(1-butyl-2-phenyl-4-thien- 3-yl-1H-imidazol-5-yl)-N,N-bis(3-ethoxybenzyl)- methanamine 966

* 1-(1-butyl-2-phenyl-4-thien- 3-yl-1H-imidazol-5-yl)-N,N-bis[4-(difluoro- methoxy)benzyl]- methanamine 624.24 1.2 967

* 2-(aminocarbonyl)-5- [(butyl{[1-butyl-4-(4- methoxyphenyl)-2-phenyl-1H-imidazol-5-yl]methyl}- amino)methyl]phenyl acetate 583.35 1.18 968

* 4-[(butyl{[1-butyl-4-(4- methoxyphenyl)-2-phenyl-1H-imidazol-5-yl]methyl}- amino)methyl]-2- hydroxybenzamide 541.33 1.16969

* 2-(aminocarbonyl)-5-{[{[1- butyl-4-(4-methoxyphenyl)-2-phenyl-1H-imidazol-5- yl]methyl}isopentyl)amino]- methyl}phenylacetate 597.36 1.21 970

* 4-{[{[1-butyl-4-(4-methoxy- phenyl)-2-phenyl-1H-imidazol-5-yl]methyl}- (isopentyl)amino]methyl}- 2-hydroxybenzamide555.35 1.18 971

* 2-(aminocarbonyl)-5-{[{[1- butyl-4-(4-methoxyphenyl)-2-phenyl-1H-imidazol-5- yl]methyl}(cyclohexylmethyl)-amino]methyl}phenyl acetate 623.38 1.24 972

* 4-{[{[1-butyl-4-(4-methoxy- phenyl)-2-phenyl-1H-imidazol-5-yl]methyl}- (cyclohexylmethyl)amino]- methyl}-2-hydroxy-benzamide 581.37 1.23 973

* 2-(aminocarbonyl)-5-[((1,3- benzodioxol-5-ylmethyl)-{[1-butyl-4-(4-methoxy- phenyl-2-phenyl- 1H-imidazol-5-yl]methyl}amino)methyl]- phenyl acetate 661.33 1.18 974

* 4-[((1,3-benzodioxol-5- ylmethyl){[1-butyl-4-(4-methoxyphenyl)-2-phenyl- 1H-imidazol-5- yl]methyl}amino)methyl]-2-hydroxybenzamide 619.32 1.17 975

* ethyl 5-{[bis(1,3-benzodioxol- 5-ylmethyl)amino]methyl}-1-butyl-2-phenyl-1H- imidazole-4-carboxylate 570.27 1.23 976

* 1-(1,3-benzodioxol-5-yl)- N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)- methyl]-N-[4-(difluoro- methoxy)benzyl]-methanamine 554.22 1.32 977

* 1-(1,3-benzodioxol-5-yl)- N-(1,3-benzodioxol-5-yl-methyl)-N-{[1-butyl-4- (methoxymethyl)-2-phenyl- 1H-imidazol-5-yl]-methyl}methanamine 542.28 1.18 978

* N-{[1-butyl-4-(4-methyl- phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}-N-[4-(difluoromethoxy)- benzyl]-N-(3-ethoxybenzyl)- amine 610.33 1.24979

* 1-(1,3-benzodioxol-5-yl)- N-{[1-butyl-4-(4-methyl-phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}- N-[4-(difluoromethoxy)-benzyl]methanamine 610.30 1.22 980

* N-{[1-butyl-4-(4-methyl- phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}-N,N-bis(3-ethoxybenzyl)- amine 588.36 1.28 981

* N-{[1-butyl-4-(4-methyl- phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}-N,N-bis[4-(difluoro- methoxy)benzyl]amine 632.30 1.21 982

* N-{[1-butyl-4-(3-methyl- phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}-N-[4-(difluoromethoxy)- benzyl]-N-(3-ethoxy- benzyl)amine 611.36 1.24983

* 1-(1,3-benzodioxol-5-yl)- N-{[1-butyl-4-(3-methyl-phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}- N-[4-(difluoromethoxy)-benzyl]methanamine 610.30 1.22 984

* N-{[1-butyl-4-(3-methyl- phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}-N,N-bis(3-ethoxy- benzyl)amine 588.36 1.27 985

* N-{[1-butyl-4-(3-methyl- phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}-N,N-bis[4-(difluoro- methoxy)benzyl]amine 632.29 1.22 986

* N-{[1-butyl-4-(4-fluoro- phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}-N-[4-(difluoromethoxy)- benzyl]-N-(3-ethoxy- benzyl)amine 614.30 1.23987

* 1-(1,3-benzodioxol-5-yl)- N-{[1-butyl-4-(4-fluoro-phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}- N-[4-(difluoromethoxy)-benzyl]methanamine 614.28 1.21 988

* N-{[1-butyl-4-(4-fluoro- phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}-N,N-bis(3-ethoxy- benzyl)amine 592.34 1.26 989

* N-{[1-butyl-4-(4-fluoro- phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}-N,N-bis[4-(difluoro- methoxy)benzyl]amine 636.28 1.2 990

* 5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-N,N-dimethyl-2- phenyl-1H-imidazole- 4-carboxamide 583.38 1.23 991

* isopropyl 5-{[bis(1,3- benzodioxol-5-ylmethyl)- amino]methyl}-1-butyl-2-phenyl-1H-imidazole- 4-carboxylate 523.37 1.31 992

* 1-(1,3-benzodioxol-5-yl)- N-(1,3-benzodioxol-5- ylmethyl)-N-{[1-butyl-4-(ethoxymethyl)-2-phenyl- 1H-imidazol-5- yl]methyl}methanamine 585.421.22 993

* 1-(1,3-benzodioxol-5-yl)- N-(1,3-benzodioxol-5- ylmethyl)-N-{[1-butyl-4-(3,5-dimethylphenyl)- 2-phenyl-1H-imidazol-5- yl]methyl}methanamine585.42 1.24 994

* 1-(1,3-benzodioxol-5-yl)- N-(1,3-benzodioxol-5- ylmethyl)-N-({1-butyl-2-phenyl-4-[3- (trifluoromethyl)phenyl]- 1H-imidazol-5-yl}methyl)methanamine 539.39 1.24 995

* 1-(1,3-benzodioxol-5-yl)-N- (1,3-benzodioxol-5-ylmethyl)-N-({1-butyl-2-phenyl-4-[3- (trifluoromethoxy)phenyl]- 1H-imidazol-5-yl}-methyl)methanamine 605.41 1.23 996

* 7-[(butyl{[1-butyl-4-(3- methoxyphenyl)-2-phenyl- 1H-imidazol-5-yl]-methyl}amino)methyl]- 2,3-dihydroquinazolin- 4(1H)-one 583.38 1.23 997

* 1-(1,3-benzodioxol-5-yl)- N-[(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]- N-[(1-methyl-1H-indol- 5-yl)methyl]methanamine523.37 1.31 998

* 1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H- imidazol-5-yl]-N-(cyclohexylmethyl)-N-(1H- indol-5-ylmethyl)- methanamine 585.42 1.22 999

* 1-(1,3-benzodioxol-5-yl)- N-[(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]- N-[(1-methyl-2,3-dihydro-1H-indol-5-yl)methyl]- methanamine 585.42 1.24 1000

* N-benzyl-1-(1-butyl-2,4-di- phenyl-1H-imidazol-5- yl)-N-[(1-methyl-1H-indol-5-yl)methyl]- methanamine 539.39 1.24 1001

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]- N-[(1-methyl-2,3-dihydro-1H-indol-5-yl)methyl]- methanamine 605.41 1.23 1002

* 1-(1,3-benzodioxol-5-yl)- N-{[1-butyl-2-phenyl-4-(trifluoromethyl)-1H- imidazol-5-yl]methyl}- N-(1H-indol-5-ylmethyl)-methanamine 561.33 1.29 1003

* N-{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H- imidazol-5-yl]methyl}-N-(1H-indol-5-yl- methyl)butan-1-amine 483.34 1.15 1004

* N-{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H- imidazol-5-yl]methyl}-N-[(1-methyl-1H-indol- 5-yl)methyl]butan-1- amine 497.35 1.18 1005

* 1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H- imidazol-5-yl]-N-(cyclohexylmethyl)-N- [(1-methyl-1H-indol-5- yl)methyl]methanamine537.39 1.37 1006

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]- N-[(1-methyl-1H-indol-5- yl)methyl]methanamine605.39 1.23 1007

* 1-(1,3-benzodioxol-5-yl)- N-{[1-butyl-2-phenyl-4-(trifluoromethyl)-1H- imidazol-5-yl]methyl}- N-[(1-methyl-1H-indol-5-yl)methyl]- methanamine 575.33 1.34 1008

* 1-(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]- N-(1H-indol-5-ylmethyl)- methanamine 591.381.2 1009

* 1-(1,3-benzodioxol-5-yl)- N-(2,1,3-benzodiazol-5-ylmethyl)-N-{[1-butyl-2- phenyl-4-(trifluoro- methyl)-1H-imidazol-5-yl]methyl}methanamine 1010

* 1-(1,3-benzodioxol-5-yl)- N-(2,1,3-benzoxadiazol-5-ylmethyl)-N-{[1-butyl- 4-(3-methoxyphenyl)-2- phenyl-1H-imidazol-5-yl)methyl}methanamine 602.36 1.2 1011

* 1-(1,3-benzodioxol-5- yl)-N-[(1-butyl-2-phenyl-1H-imidazol-5-yl)methyl]- N-(3-ethoxybenzyl)- methanamine 498.33 1.191012

* 1-(1,3-benzodioxol-5- yl)-N-[(1-butyl-2-phenyl-1H-imidazol-5-yl)methyl]- N-[3-(1,1,2,2-tetrafluoro- ethoxy)benzyl]-methanamine 570.30 1.18 1013

* 1-(1,3-benzodioxol-5- yl)-N-[(1-butyl-4-ethoxy-2-phenyl-1H-imidazol-5- yl)methyl]-N-(3-ethoxy- benzyl]methanamine257.21 1.21 1014

* 1-(1,3-benzodioxol-5- yl)-N-[(4-bromo-1-butyl- 2-phenyl-1H-imidazol-5-yl)methyl]-N-(3-ethoxy- benzyl)methanamine 576.27 1.35 1015

* 1-(1,3-benzodioxol-5- yl)-N-[(4-bromo-1-butyl- 2-phenyl-1H-imidazol-5-yl)methyl]-N-[3-(1,1,2,2- tetrafluoroethoxy)- benzyl]methanamine 648.251.34 1016

* 1-(5-{[bis(1,3-benzodioxol- 5-ylmethyl)amino]methyl}-1-butyl-2-phenyl-1H- imidazol-4-yl)ethanol 1017

* N-{[1-butyl-4-(3-fluoro- phenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}-N-[4-(difluoro- methoxy)benzyl]-N-(3- ethoxybenzyl)amine 1018

* 1-(1,3-benzodioxol-5- yl)-N-{[1-butyl-4-(3- fluorophenyl)-2-phenyl-1H-imidazol-5-yl]methyl}- N-[4-(difluoromethoxy)- benzyl]methanamine1019

* N-{[1-butyl-4-(3-fluoro- phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}-N,N-bis(3-ethoxybenzyl)- amine 1020

* N-{[1-butyl-4-(3-fluoro- phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}-N,N-bis[4-(difluoro- methoxy)benzyl]amine 1021

* N-{[1-butyl-4-(4-ethoxy- phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}-N-[4-(difluoromethoxy)- benzyl]-N-(3-ethoxy- benzyl)amine 1022

* 1-(1,3-benzodioxol-5-yl)- N-{[1-butyl-4-(4-ethoxy-phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}- N-[4-(difluoromethoxy)-benzyl]methanamine 1023

* N-{[1-butyl-4-(4-ethoxy- phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}-N,N-bis(3-ethoxy- benzyl)amine 1024

* N-{[1-butyl-4-(4-ethoxy- phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}-N,N-bis[4-(difluoro- methoxy)benzyl]amine 1025

* 1-[1-butyl-4-(3,4-difluoro- phenyl)-2-phenyl-1H- imidazol-5-yl]-N-[4-(difluoromethoxy)benzyl]- N-(3-ethoxybenzyl)- methanamine 1026

* 1-(1,3-benzodioxol-5-yl)- N-{[1-butyl-4-(3,4-difluoro-phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}- N-[4-(difluoromethoxy)-benzyl]methanamine 1027

* 1-[1-butyl-4-(3,4-difluoro- phenyl)-2-phenyl-1H- imidazol-5-yl]-N,N-bis(3-ethoxybenzyl)- methanamine 1028

* 1-[1-butyl-4-(3,4-difluoro- phenyl)-2-phenyl-1H- imidazol-5-yl]-N,N-bis[4-(difluoromethoxy)- benzyl]methanamine 1029

* N-{[1-butyl-4-(3-chloro- phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}-N-[4-(difluoromethoxy)- benzyl]-N-(3-ethoxy- benzyl)amine 1030

* 1-(1,3-benzodioxol-5- yl)-N-{[1-butyl-4-(3- chlorophenyl)-2-phenyl-1H-imidazol-5-yl]methyl}- N-[4-(difluoromethoxy)- benzyl]methanamine1031

* N-{[1-butyl-4-(3-chloro- phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}-N,N-bis(3-ethoxybenzyl)- amine 1032

* N-{[1-butyl-4-(3-chloro- phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}-N,N-bis[4-(difluoro- methoxy)benzyl]amine 1033

* N-{[1-butyl-4-(4-chloro- phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}-N-[4-(difluoromethoxy)- benzyl]-N-(3-ethoxy- benzyl)amine 1034

* 1-(1,3-benzodioxol-5-yl)- N-{[1-butyl-4-(4-chloro-phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}- N-[4-(difluoromethoxy)-benzyl]methanamine 1035

* N-{[1-butyl-4-(4-chloro- phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}-N,N-bis(3-ethoxybenzyl)- amine 1036

* N-{[1-butyl-4-(4-chloro- phenyl)-2-phenyl-1H- imidazol-5-yl]methyl}-N,N-bis[4-(difluoro- methoxy)benzyl]amine 1037

* 1-(1,3-benzodioxol-5-yl)- N-(1,3-benzodioxol-5-ylmethyl)-N-{[1-butyl-4- (3-chlorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}methanamine 1038

* 1-(1,3-benzodioxol-5-yl)- N-(1,3-benzodioxol-5-ylmethyl)-N-{[1-butyl-4- (4-chlorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}methanamine 1039

* 1-(1,3-benzodioxol-5-yl)- N-(1,3-benzodioxol-5-ylmethyl)-N-{[1-butyl-4- (3-fluorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}methanamine 1040

* 1-(1,3-benzodioxol-5-yl)- N-(1,3-benzodioxol-5-ylmethyl)-N-{[1-butyl-4- (3-methylphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}methanamine 1041

* 1-(5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-2-phenyl-1H- imidazol-4-yl)ethanone 1042

* 5-{[bis(1,3-benzodioxol-5- ylmethyl)amino]methyl}-1-butyl-2-phenyl-1H- imidazol-4-carbaldehyde 1043

* 1-(1,3-benzodioxol-5-yl)- N-(1,3-benzodioxol-5- ylmethyl}-N-{[1-butyl-2-phenyl-4-(phenylthio)- 1H-imidazol-5- yl]methyl}methanamine 1044

* ethyl 5-({(1,3-benzodioxol- 5-ylmethyl)[(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]amino}methyl)- indoline-1-carboxylate1045

* ethyl 5-({[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl][4-(difluoro- methoxy)benzyl]amino}- methyl)indoline-1-carboxylate 1046

N-benzyl-1-(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)-N-[2-chloro-3-(tri-fluoromethyl)benzyl]- methanamine

TABLE III CMP Ca2+ # STRUCTURE Mob. IUPAC NAME MASS 1047

* 7-({butyl[(1-butyl-4-chloro-2-phenyl- 1H-imidazol-5-yl)methyl]amino}methyl}quinazolin- 4-ol 478.037 1048

* 1-(1,3-benzodioxol-5-yl)-N-{[2-(1,3-benzodioxol-5-yl)-1-butyl-4-phenyl- 1H-imidazol-5-yl]methyl}-N-(1,3-benzodioxol-5- ylmethyl)methanamine 617.698 1049

* 1-(1,3-benzodioxol-5-yl)-N-(1,3-benzodioxol-5-ylmethyl)-N-{[1-butyl-2- (1-naphthyl)-4-phenyl-1H-imidazol-5- yl]methyl}methanamine 623.749 1050

* 1-(1,3-benzodioxol-5-yl)-N-(1,3-benzodioxol-5-ylmethyl)-N-{[1-butyl-2-(2-naphthyl)-4-phenyl-1H-imidazol-5- yl]methyl}methanamine 623.749 1051

* 1-(1,3-benzodioxol-5-yl)-N-(1,3-benzodioxol-5-ylmethyl)-N-{[1-butyl-2- (3-ethoxyphenyl}-4-phenyl-1H-imidazol-5-yl]methyl}methanamine 617.742 1052

* 1-(1,3-benzodioxol-5-yl)-N-(1,3-benzodioxol-5-ylmethyl)-N-[[1-butyl-2- {2-fluorophenyl)-4-phenyl-1H-imidazol-5-yl]methyl}methanamine 591.68 1053

* 1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[[1-butyl-2- (3-methylphenyl)-4-phenyl-1H-imidazol-5-yl]methyl}methanamine 587.716 1054

* 1-(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)-N,N-bis(cyclohexylmethyl)methanamine 497.765 1055

* 1-(1,3-benzodioxol-5-yl)-N-(1,3-benzodioxol-5-ylmethyl)-N-[[1-butyl-2- (2-methoxyphenyl)-4-phenyl-1H-imidazol-5-yl] methyl}methanamine 603.715 1056

* 1-[1-butyl-2-(2-methoxyphenyl)-4- phenyl-1H-imidazol-5-yl]-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)- N-{3-ethoxybenzyl)methanamine617.786 1057

* N-{[1-butyl-2-(2-methylphenyl)-4- phenyl-1H-imidazol-5-yl]methyl}-N-(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)-N-(3-ethoxybenzyl)amine601.787 1058

* 5-[[bis(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]methyl]-1-butyl-2- phenyl-1H-imidazole-4-carbonitrile550.656 1059

* N-[(1-butyl-4-fluoro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl]amine 529.652 1060

* N-[(1-butyl-4-fluoro-2-phenyl-1H- imidazol-5-yl)methyl]-N,N-bis(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amine 543.636 1061

* 4-({butyl[(1-butyl-4-chloro-2-phenyl- 1H-imidazol-5-yl)methyl]amino}methyl)benzenesulf- onamide 489.081 1062

* 4-({butyl[(1-butyl-4-chloro-2-phenyl- 1H-imidazol-5-yl)methyl]amino}methyl)benzamide 453.027 1063

* methyl 2-amino-4-({butyl[(1-butyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)benzoate 524.705 1064

* 7-({butyl[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl]amino}methyl)quinazolin-4- ol 519.689 1065

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(tetrahydro-2H-pyran-4- ylmethyl)amine 510.074 1066

* 1-(5-butyl-3-chloro-6-phenylpyridazin-4-yl)-N-(2,3-dihydro-1,4-benzodioxin- 5-ylmethyl)-N-(3-ethoxybenzyl)methanamine 558.118 1067

* 1-(5-butyl-3-ethoxy-6- phenylpyridazin-4-yl)-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)methanamine 567.726 1068

* N-(1,3-benzodioxol-5-ylmethyl)-N-[(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]-4-isopropylaniline 557.7341069

* 1-[1-butyl-2-(2-methoxyphenyl)-4-(trifluoromethyl)-1H-imidazol-5-yl]-N- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)methanamine 609.685 1070

* 4-({(1,3-benzodioxo-5-ylmethyl)[(1- butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl]amino}methyl)-N,N- dimethylcyclohexanamine 578.796 1071

* 1-(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N-(tetrahydro-2H-pyran-4- ylmethyl)methanamine 551.727 1072

* 1-(5-butyl-3-morpholin-4-yl-6- phenylpyridazin-4-yl)-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)methanamine 608.779 1073

* N-1-(5-butyl-4[[(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)(3-ethoxybenzyl)amino]methyl)-6- phenylpyridazin-3-yl)-N-2-,N-2-dimethylethane-1,2-diamine 609.81 1074

* N-{[1-butyl-2-(2-methylphenyl)-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)amine 593.686 1075

* N-[1-(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)ethyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)amine 560.134 1076

* 1 -(1,3-benzodioxol-5-yl)-N-(1,3-benzodioxol-5-ylmethyl)-N-{[1-butyl-4- chloro-2-(2-methoxyphenyl)-1H-imtdazol-5-yl]methyl}methanamine 562.063 1077

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-1-(3-ethoxyphenyl)ethanamine 560.134 1078

* 1-(5-butyl-6-phenyl-3-pyrrolidin-1-ylpyridazin-4-yl)-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-N-methylmethanamine 472.629 1079

* 1-(5-butyl-6-phenyl-3-piperidin-1-ylpyridazin-4-yl)-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-N-methylmethanamine 486.656 1080

* methyl 4-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)amino]methyl}- cyclohexanecarboxylate 566.138 1081

* 4-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}- cyclohexanecarboxlic acid 552.111 1082

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-1-(2,3-dihydro- 1,4-benzodioxin-6-yl)-N-(3-ethoxybenzyl)ethanamine 560.134 1083

* N-[(5-butyl-6-phenylpyrimidin-4- yl)methyl]-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)amine 523.673 1084

* N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(cyclopropylmethyl)-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)amine466.022 1085

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-[(6-methoxypyridin-3-yl)methyl]amine 533.069 1086

* 5-butyl-4-{[(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)(methyl)amino]methyl}-6- phenyl-N,N-dipropylpyridazin-3- amine502.699 1087

* 1-[3-chloro-5-methyl-6-(2- methylphenyl)pyridazin-4-yl]-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)- N-(3-ethoxybenzyl)methanamine530.065 1088

* 5-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}pyridin-2-ol 519.042 1089

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(3-propoxybenzyl)amine 560.134 1090

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(3-isopropoxybenzyl)amine 560.134 1091

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(1H-indazol-6-ylmethyl)amine 542.08 1092

* methyl 4-([[(1-butyl-4-chloro-2- phenyl-1H-imidazol-5-yl)methyl][(2-methyl-1,3-benzothiazol-5- yl)methyl]amino)methyl)benzoate 573.158 1093

* 4-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}benzoic acid 546.064 1094

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N-[(3,5- dimethyl-1H-pyrazol-4-yl)methylamine 520.074 1095

* 1-(2,3-dihydro-1,4-benzodioxin-6-yl)-N-(3-ethoxybonzyl)-N-{[5-methyl-6-(2- methylphenyl)-3-pyrrolidin-1-ylpyridazin-4-yl]methyl}methanamine 564.726 1096

* 1-(2,3-dihydro-1,4-benzodioxin-6-yl)-N-(3-ethoxybenzyl)-N-{[5-methyl-6-(2- methylphenyl)-3-piperidin-1-ylpyridazin-4-yl]methyl}methanamine 578.753 1097

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-[(6-methoxypyridin-2-yl)methyl]amine 533.069 1098

* 4-({[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl][(2-methyl-1,3- benzothiazol-5-yl)methyl]amino}methyl)benzoic acid 559.131 1099

* 3-[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]propan-1-ol 470.01 1100

* 1-(5-butyl-6-phenyl-3-pyrrolidin-1-ylpyridazin-4-yl)-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)methanamine 592.78 1101

* 1-(5-butyl-6-phenyl-3-piperidin-1-ylpyridazin-4-yl)-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)methanamine 606.806 1102

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(1H-indazol-5-ylmethyl)amine 542.08 1103

* 1-(5-butyl-3-isopropoxy-6- phenylpyridazin-4-yl)-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)methanamine 581.753 1104

* 1-(5-butyl-3-isobutoxy-6- phenylpyridazin-4-yl)-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)methanamine 595.779 1105

* 4-[(5-butyl-4-{[(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)(3-ethoxybenzyl)amino]methyl}-6- phenylpyridazin-3-yl)oxy]-2-methylbutan-2-ol 625.805 1106

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-3-morpholin-4-ylpropan-1-amine 539.116 1107

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-[(5-methoxypyridin-3-yl)methyl]amine 533.069 1108

* N-[(5-butyl-3-cbloro-6- phenylpyridazin-4-yl)methyl]-N-(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)butan-1-amine 480.049 1109

* N-[(5-butyl-6-phenyl-3-piperidin-1- ylpyridazin-4-yl)methyl]-N-{2,3-dihydro-1,4-benzodioxin-6- ylmethyl)butan-1-amine 528.737 1110

* N-[(5-butyl-3-isobutoxy-6- phenylpyridazin-4-yl)methyl]-N-(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)butan-1-amine 517.71 1111

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-2-cyclopropyl-N- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)ethanamine 480.049 1112

* N-[(4-chloro-2-phenyl-1-propyl-1H-imidazol-5-yl)methyl]-1-(2,3-dihydro- 1,4-benzodioxin-6-yl)-N-(3-ethoxybenzyl)ethanamine 546.107 1113

* N,5-dibutyl-4-{[butyl(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}-6- phenylpyridazin-3-amine 516.726 1114

* N-{[5-butyl-3-(4-methylpiperazin-1-yl)-6-phenylpyridazin-4-yl]methyl)-N-(2,3- dihydro-1,4-benzodioxin-6-ylmethyl)butan-1-amine 543.752 1115

* 1-butyl-5-{[(2,3-dihydro-1,4- benzodioxin-6-ylmethyl}(3-ethoxybenzyl)amino]methyl)-2-(2- methoxyphenyl)-1H-imidazole-4-carbonitrile 566.698 1116

* N-{[4-chloro-1 -methyl-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}-1-(2,3-dihydro-1,4- benzodioxin-6-yl)-N-(3-ethoxybenrzl)ethanamine 532.081 1117

* N-{[5-butyl-3-(2-methoxyethoxy)-6-phenylpyridazin-4-yl]methyl}-N-(2,3- dihydro-1,4-benzodioxin-6-ylmethyl)butan-1-amine 519.682 1118

* N-(1,3-benzodioxol-5-ylmethyl)-N-[(1-methyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]butan-1-amine 453.583 1119

* 1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(1-methyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]methanamine 531.609 1120

* N-(1,3-benzodioxol-5-ylmethyl)-N-[(1-ethyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]butan-1-amine 467.61 1121

* 1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(1-ethyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]methanamine 545.636 1122

* N-(1,3-benzodioxol-5-ylmethyl)-N- [(2,4-diphenyl-1-propyl-1H-imidazol-5-yl)methyl]butan-1-amine 481.637 1123

* 1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(2,4-diphenyl-1-propyl-1H-imidazol-5- yl)methyl]methanamine 559.663 1124

* 1-butyl-5-{[(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)(3-ethoxybenzyl)amino]methyl}-2- phenyl-1H-imidazole-4-carbonitrile 536.6721125

* 1-(1,3-benzodioxol-5-yl)-N-(1,3-benzodioxol-5-ylmethyl)-N-{[1-butyl-2- (3,5-dimethyl-1H-pyrazol-1-yl)-4-phenyl-1H-imidazol-5- yl]methyl}methanamine 591.708 1126

* 1-[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5-yl]-N-(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)-N-(3- ethoxybenzyl)methanamine550.134 1127

* 1-(1,3-benzodioxol-5-yl)-N-(1,3-benzodioxol-5-ylmethyl)-N-{[1-butyl-4- chloro-2-(2-methylphenyl)-1H-imidazol-5-yl]methyl}methanamine 546.064 1128

* 1-butyl-4-chloro-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)-2-phenyl-1H-imidazol- 5-amine 532.081 1129

* 1-(4-chloro-2-phenyl-1-propy1-1H- imidazol-5-yl)-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)methanamine 532.081 1130

* 1-(4-chloro-2-phenyl-1-propyl-1H- imidazol-5-yl)-N,N-bis(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)methanamine 546.064 1131

* 1-(1,3-benzodioxol-5-yl)-N-[(4-chloro-2-phenyl-1-propyl-1H-imidazol-5- yl)methyl]-N-(3-ethoxybenzyl)methanamine 518.054 1132

* 1-(1,3-benzodioxol-5-yl)-N-(1,3- benzodioxol-5-ylmethyl)-N-[(4-chloro-2-phenyl-1-propyl-1H-imidazol-5- yl)methyl]methanamine 518.01 1133

* 1-(2,3-dihydro-1,4-benzodioxin-6-yl)-N-(3-ethoxybenzyl)-N-[(1-rnethyl-2,4- diphenyl-1H-imidazol-5-yl)methyl]methanamine 545.68 1134

* 1-(2,3-dihydro-1,4-benzodioxin-6-yl)-N-(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)-N-[(1-methyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]methanamine 559.663 1135

* 1-(1,3-benzodioxo1-5-yl)-N-(3- ethoxybenzyl)-N-[(1-methyl-2,4-diphenyl-1H-imidazol-5- yl)methyl]methanamine 531.653 1136

* 1-(2,3-dihydro-1,4-benzodioxin-6-yl)- N-[(2,4-diphenyl-1-propyl-1H-imidazol-5-yl)methyl]-N-(3- ethoxybenzyl)methanamine 573.733 1137

* 1-(2,3-dihydro-1,4-benzodioxin-6-yl)-N-(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)-N-[(2,4-diphenyl-1-propyl-1H-imidazol-5- yl)methyl]methanamine 587.716 1138

* 1-(1,3-benzodioxol-5-yl)-N-[(2,4- diphenyl-1-propyl-1H-imidazol-5-yl)methyl]-N-(3- ethoxybenzyl)methanamine 559.706 1139

* 1-(1,3-benzodioxol-5-yl)-N-{[1-butyl-4- fluoro-2-(2-methylphenyl)-1H-imidazol-5-yl]methyl}-N-(3- ethoxybenzyl)methanamine 529.652 1140

* 1-[1-butyl-4-fluoro-2-(2- methylphenyl)-1H-imidazol-5-yl]-N-(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)-N-(3- ethoxybenzyl)methanamine543.679 1141

* 1-(1,3-benzodioxol-5-yl)-N-(1,3-benzodioxol-5-ylmethyl)-N-{[1-butyl-2- (2-chlorophenyl)-4-phenyl-1H-imidazol-5-yl]methyl}methanamine 608.135 1142

* N-{[1-butyl-2-(2-chlorophenyl)-4- phenyl-1H-imidazol-5-yl]methyl)-N-(2,3-dihydro-1,4-benzocdioxin-6- ylmethyl)-N-(3-ethoxybenzyl)amine622.205 1143

* 5-{[(1,3-benzodioxol-5-ylmethyl)(3-ethoxybenzyl)amino]methyl)-1-butyl- 2-(2-methylphenyl)-1H-imidazole-4-carbonitrile 536.672 1144

* 1-butyl-5-{[(2,3-dihydro-1,4- benzodioxin-6-ylmethyl}(3-ethoxybenzyl)amino]methyl)-2-(2- methylphenyl)-1H-imidazole-4-carbonitrile 550.699 1145

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(2-fluoro-5-methoxybenzyl)amine 550.071 1146

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(4-fluoro-3-methoxybenzyl)amine 550.071 1147

* N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,6-difluorobenzyl)-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amine 538.0351148

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(3-fluorobenzyl)amine 520.045 1149

* N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-{3-chlorobenzyl)-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amine 536.51150

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(3-methylbenzyl)amine 516.082 1151

* 1-(3-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}phenyl)ethan one 544.092 1152

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(3-methoxybenzyl)amine 532.081 1153

* 3-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}benzoic acid 546.064 1154

* 3-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}benzamide 545.08 1155

* 3-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}benzonitrile 527.065 1156

* N-[(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)methyl]-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2- methoxyethanamine 511.662 1157

* N-[(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)methyl]-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-3- methoxypropan-1-amine 525.689 1158

* N-[(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)methyl]-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2- ethoxyethanamine 525.689 1159

* 4-[[(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]butan- 1-ol 525.689 1160

* N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3dihydro-1,4-benzodioxin-6-ylmethyl)-2- methoxyethanamine 470.01 1161

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-3-methoxypropan-1-amine 484.037 1162

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-2-ethoxyethanamine 484.037 1163

* 4-[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]butan- 1-ol 484.037 1164

* 1-[1-butyl-2-(2-methyl-1,3-thiazol-4-yl)-4-phenyl-1H-imidazol-5-yl]-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl )- N-(3-ethoxybenzyl)methanamine608.803 1165

* 1-[4-chloro-1-methyl-2-(2- methylphenyl)-1H-imidazol-5-yl]-N-(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)-N-(3- ethoxybenzyl)methanamine518.054 1166

* 1-[4-chloro-1-methyl-2-(2- methylphenyl)-1H-imidazol-5-yl]-N-(3-ethoxybenzyl)-N-(1H-indol-5- ylmethyl)methanamine 499.055 1167

* 1-[1-butyl-4-chloro-2-(4-fluorophenyl)-1H-imidazol-5-y]l-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)methanamine 564.097 1168

* 1-(4-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}phenyl)-ethan one 544.092 1169

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(4-methylbenzyl)amine 516.082 1170

* N-[(4-bromo-1-butyl-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)amine 590.558 1171

* N-[(1-butyl-4-methyl-2-phenyl-1H- imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)amine 525.689 1172

* l-[1-butyl-4-fluoro-2-(2- methylphenyl)-1H-imidazol-5-yl]-N-(3-ethoxybenzyl)-N-(1H-indol-5- ylmethyl)methanamine 524.68 1173

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(1H-indol-5-ylmethyl)amine 541.092 1174

* 1-(2,3-dihydro-1,4-benzodioxin-6-yl)-N-(3-ethoxybenzyl)-N-[(4-methyl-2- phenyl-1-propyl-1H-imidazol-5-yl)methyl]methanamine 511.662 1175

* 6-{[[(l-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl)-1,2- benzisoxazol-3-amine 558.079 1176

* 593.643 1177

* 560.091 1178

* 2-[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]-1-(3- methoxyphenyl)ethanone 560.091 1179

* N-2-butyl-N-2-[(1-butyl-4-chloro- 2-phenyl-1H-imidazol-5-yl)methyl]-N-1-(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)glycinamide 525.089 1180

* 2-[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]-1-(3- methoxyphenyl)ethanol 562.106 1181

* N-[2-(benzyloxy)ethyl]-N-[(1-butyl-4- chloro-2-phenyl-1H-imidazol-5-yl)methyl]butan-1-amine 454.054 1182

* N-[2-(benzyloxy)ethyl]-N-[(1-butyl-4- chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amine 546.107 1183

* methyl 3-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)amino]methyl}benzoate 560.091 1184

* 5-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}-N-(2- methoxyethyl)pyridin-2-amine 576.137 1185

* N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N-[(6- morpholin-4-ylpyridin-3-yl)methyl]amine 588.148 1186

* N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-[(6-chloropyridin-3-yl)methyl]-N-(2,3- dihydro-1,4-benzodioxin-6-ylmethyl)amine 537.488 1187

* 4-{[[(5-butyl-3-chloro-6- phenylpyridazin-4-yl)methyl](2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino]rnethyl)benzoic acid 558.0751188

* 1-(5-butyl-2-methoxy-6- phenylpyrimidin-4-yl)-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)methanamine 553.699 1189

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-2-(2,3-dihydro- 1,4-benzodioxin-6-yl)-N-(3-ethoxybenzyl)propan-2-amine 574.161 1190

* 4-{[[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5yl)methyl](2,3-dihydro-1,4- benzodioxin-6- ylmethyl)amino]methyl}-3-chlorobenzoic acid 580.509 1191

* 4-({[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl][1-(2,3-dihydro- 1,4-benzodioxin-6-yl)ethyl]amino}methyl)benzoic acid 560.091 1192

* 4-{[[(5-butyl-3-isopropoxy-6- phenylpyridazin-4-yl)methyl](2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid 581.7091193

* 4-({butyl[(1-butyl-4-chloro-2-phenyl- 1H-imidazol-5-yl)methyl]amino}methyl)-3- chlorobenzoic acid 488.456 1194

* N-[(1-butyl-2,4-diphenyl-1H-imidazol- 5-yl)methyl]-N-methyl-1,2,3,4-tetrahydronaphthalen-l-amine 449.638 1195

* 4-({[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl][4-(difluoromethoxy)benzyl]amino}methyl)- benzoic acid 554.034 1196

* 5-butyl-4-{[(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)(3-ethoxybenzyl)amino]methyl}-6- phenylpyrimidin-2-ol 539.672 1197

* 4-{[[(5-butyl-3-isobutoxy-6- phenylpyridazin-4-yl)methyl](2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino]rnethyl}benzoic acid 595.7361198

* N-[{1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(1H-pyrazol-4-ylmethyl)amine 492.02 1199

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-[(1-ethyl-1H-pyrazol-yl)methyl]amine 520.074 1200

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(1H-pyrazol-5-ylmethyl)amine 492.02 1201

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-{2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N-[(1,4- dimethyl-1H-pyrazol-3-yl)methyl]amine 520.074 1202

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-(pyridin-4-ylmethyl)amine 503.043 1203

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N-[4-(1H- tetraazol-5-yl)benzyl]amine570.094 1204

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-[(1-oxidopyridin-4-yl)methyl]amine 519.042 1205

* N-[(1-butyl-4-chloro-2-phenyl-1H- imidazol-5-yl)methyl]-N-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)methyl]- N-(2,3-dihydo-1,4-benzodioxin-6-ylmethyl)amine 554.519 1206

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-{[5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol- 4-yl]methyl}-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amine 608.489 1207

* 4-{[[(5-butyl-2-methoxy-6- phenylpyrimidin-4-yl)methyl](2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid 553.6561208

* 4-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}-3- fluorobenzoic acid 564.054 1209

* 4-{[[(5-butyl-2-isopropoxy-6- phenylpyrimidin-4-yl)methyl](2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid 581.7091210

* 4-{[[(5-butyl-2-isopropoxy-6- phenylpyrimidin-4-yl)methyl](2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid 595.7361211

* 4-{[[(5-butyl-3-chloro-6- phenylpyridazin-4-yl)methyl][4-(difluoromethoxy)benzylamino}- methyl)benzoic acid 566.045 1212

* 5-{3-[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]propyl}isoxazol-3-ol 537.057 1213

* 5-{5-[[(1 -butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]pentyl}isoxazol-3-ol 565.11 1214

* 4-{[[(5-butyl-3-chloro-6- phenylpyridazin-4-yl)methyl](2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}-3- fluorobenzoic acid576.065 1215

* 4-{[[(5-butyl-3-chloro-6- phenylpyridazin-4-yl)methyl](2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}-3- chlorobenzoic acid592.52 1216

* 4-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl)-2- fluorobenzoic acid 564.054 1217

* N-[(l-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-N-[(4-methyl-3,4-dihydro-2H-1,4- benzoxazin-6-yl)methyl]amine 573.133 1218

* 6-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}nicotinic acid 547.052 1219

* methyl 4-{[{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}benzoate 574.117 1220

* 4-{[{1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)amino]methyl}benzoicacid 560.091 1221

* methyl 4-{[[(4-chloro-2-phenyl-1- propyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino}methyl}benzoate 546.064 1222

* methyl 4-{[{[l-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}benzoate 593.643 1223

* methyl 4-{[[(1-butyl-4-cyano-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)amino]methyl}benzoate 550.656 1224

* methyl 4-{[[(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}benzoate 601.743 1225

* methyl 4-{[[(1-butyl-4-methyl-2- phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoate 539.672 1226

* methyl 4-{{(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)[(4-methyl-2-phenyl-1-propyl-1H-imidazol-5- yl)methyl]amino}methyl}benzoate 525.6461227

* 4-{[[(4-chloro-2-phenyl-1-propyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}benzoic acid 532.037 1228

* 4-{[{[1-butyl-2-phenyl-4- (trifluoromethyl)-1H-imidazol-5-yl]methyl}(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)amino]methyl}benzoicacid 579.616 1229

* 4-{[[(1-butyl-4-cyano-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}benzoic acid 536.629 1230

* 4-{[[(1-butyl-2,4-diphenyl-1H- imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid 587.716 1231

* 4-{[[(1-butyl-4-methyl-2-phenyl-1H-imidazol-5-yl}methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}benzoic acid 525.646 1232

* 4-({(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)[(4-methyl-2-phenyl-1 -propyl-1H-imidazol-5- yl)methyl]amino}methyl)benzoic acid 511.619 1233

* methyl 4-{[{[1-butyl-4-cyano-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}benzoate 564.682 1234

* methyl 4-{[{[1-butyl-4-fluoro-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}(3- ethoxybenzyl)amino]methyl}benzoate 543.679 1235

* 4-{[{[1-butyl-4-cyano-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)amino]methyl}benzoicacid 550.656 1236

* 4-{[{[1-butyl-4-fluoro-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}(3- ethoxybenzyl)amino]methyl}- benzoic acid 529.652 1237

* 4-{[{[1-butyl-4-fluoro-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)amino]methyl}benzoicacid 543.636 1238

* methyl 4{[{[1-butyl-4-fluoro-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}benzoate 557.662 1239

* N-{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}-N-(1H-indol-5-ylmethyl)-3- methylbutan-1-amine 477.092 1240

* N-{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}-N-(1H-indol-5- ylmethyl)butan-1-amine 463.065 1241

* methyyl-{[[(1-butyl-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amine]methyl}benzoate 525.646 1242

* 4-{[[(1-butyl-2-phenyl-1H-imidazol-5- yl)methyl](2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid 511.619 1243

* methyl 4-{[[(4-bromo-1-butyl-2- phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoate 604.542 1244

* 4-{[[(4-bromo-1-butyl-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}benzoic acid 590.515 1245

* N-{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}-N-{2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-3-methylbutan-1-amine 496.091 1246

* methyl 4-{[{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}(isopentyl)amino]methyl}- benzoate 496.091 1247

* 4-{[{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}(isopentyl)amino]methyl}- benzoic acid 482.064 1248

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)-3-methylbutan-1-amine 482.064 1249

* methyl 2-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)amino]methyl}benzoate 560.091 1250

* methyl 6-[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)amino]hexanoate 540.1 1251

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)prop-2-yn-1-amine 449.979 1252

* N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)prop-2-en-1-amine 451.995 1253

* ethyl 2-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6-ylmethyl)amino]rnethyl}cyclopropane carboxylate 538.084 1254

* 2-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}benzoic acid 546.064 1255

* 6-[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]hexanoic acid 526.073 1256

* ethyl 4-{3-[[(1-butyl-4-chloro-2- phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino]propyl}benzoate 602.171 1257

* ethyl 4-(3-{butyl[(4-chloro-2-phenyl-1- propyl-1H-imidazol-5-yl)methyl]amino}propyl)benzoate 496.091 1258

* ethyl 4-[3-(butyl{[1-butyl-4-chloro-2- (2-methylphenyl)-1H-imidazol-5-yl]methyl}amino)propyl]benzoate 524.145 1259

* 4-{3-[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]propyl}benzoic acid 574.117 1260

* 4-[3-(butyl{[1-butyl-4-chloro-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}amino)propyl]benzoic acid 496.091 1261

* methyl (4-{[[(1-butyl-4-chloro-2- phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}phenyl)acetate 574.1171262

* methyl 2-(4-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3- dihydro-1,4-benzodioxin-6-ylmethyl)amino]methyl}phenyl)propanoate 588.144 1263

* methyl 2-(4-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3- dihydro-1,4-benzodioxin-6-ylmethyl)amino]methyl}phenyl)-2- methylpropanoate 602.171 1264

* methyl (3-{[[(1-butyl-4-chloro-2- phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl}phenyl)- acetate574.117 1265

* (4-{[[(1-butyl-4-chlo ro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}phenyl)acetic acid 560.091 1266

* 2-(4-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}phenyl)propanoic acid 574.117 1267

* 2-(4-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}phenyl)-2- methylpropanoic acid 588.144 1268

* (3-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6-ylmethyl)amino]methyl}phenyl)acetic acid 560.091 1269

* 5-(5-{butyl[(1-butyl-4-chloro-2-phenyl- 1H-imidazol-5-yl)methyl]amino}pentyl)isoxazol-3-ol 473.057

TABLE IV LCMS LCMS Cmp. # MOLSTRUCTURE IUPAC Name (min.) MW Mass 1270

methyl 4-{[{[1-butyl-4- chloro-2-(2- methylphenyl)-1H- imidazol-5-yl]methyl}(neopentyl) amino] methyl}-2- methoxybenzoate 1.36 526.12525.28 1271

4-{[{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}(neopentyl) amino] methyl}-2- methoxybenzoic acid 1.32 512.09511.26 1272

4-{[{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}(neopentyl)amino] methyl}-2- methoxybenzamide 1.31 511.11 510.28 1273

4-{[{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}(neopentyl) amino] methyl}-2- hydroxybenzamide 1.31 497.08 496.261274

4-{[{[1-butyl-4-(4- methoxyphenyl)-2- phenyl-1H-imidazol-5- yl]methyl}(neopentyl)amino] methyl}-2- hydroxybenzamide 1.19 554.73 554.33 1275

4-[(benzyl{[1-butyl-4-(4- methoxy phenyl)-2- phenyl-1H-imidazol-5-yl]methyl}amino) methyl]-2- hydroxybenzamide 1.18 574.72 574.29 1276

methyl (4-{[[(1-butyl-4- chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6- ylmethyl)amino] methyl}phenyl)acetate 1.29 574.12 573.24 1277

methyl 2-(4-{[[(1-butyl- 4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}phenyl) propanoate 1.31 588.14 587.26 1278

methyl 2-(4-{[[(1-butyl- 4-chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}phenyl)-2- methylpropanoate 1.33 602.17 601.27 1279

methyl (3-{[[(1-butyl-4- chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6- ylmethyl)amino] methyl}phenyl)acetate 1.29 574.12 573.24 1280

(4-{[[(1-butyl-4-chloro-2- phenyl-1H-imidazol-5- yl)methyl](2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino] methyl}phenyl)acetic acid 1.24 560.09 559.22 1281

2-(4-{[[(1-butyl-4-chloro- 2-phenyl-1H-imidazol-5- yl)methyl](2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino] methyl}phenyl)propanoic acid 1.26 574.12 573.24 1282

2-(4-{[[(1-butyl-4-chloro- 2-phenyl-1H-imidzol-5- yl)methyl](2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}phenyl)-2- methylpropanoic acid 1.28 588.14 587.26 1283

(3-{[[(1-butyl-4-chloro-2- phenyl-1H-imidazol-5- yl)methyl](2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl} phenyl) acetic acid 1.25560.09 559.22 1284

N-{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}-N-(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)butan-1- amine 1.16 482.06481.25 1285

4-[(butyl{[1-butyl-4- chloro-2-(2-methyl phenyl)-1H-imidazol-5-yl]methyl}amino) methyl]benzene sulfonamide 1.17 503.11 502.22 1286

4-{[{[1-butyl-4-chloro-2- (2-methyl phenyl)-1H- imidazol-5-yl] methyl}(isopentyl)amino] methyl}benzene sulfonamide 1.2 517.13 516.23 1287

4-{[[(1-butyl-4-chloro-2- phenyl-1H-imidazol-5- yl) methyl](2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino] methyl}benzene sulfonamide 1.24581.13 580.19 1288

N-{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}-N-[(3-chloro-1H-indol-5- yl)methyl]-3- methylbutan-1-amine 1.18 511.54510.23 1289

5-{[{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}(isopentyl) amino]methyl}-1H- indole-3-carbonitrile 1.15 502.10501.27 1290

4-{[{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)amino] methyl}benzenesulfonamide 1.24 595.16 594.21 1291

N-{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}-N-(quinoxalin-6- ylmethyl)butan-1- amine 1.25 476.07 475.25 1292

methyl [[(1-butyl-4- chloro-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino](phenyl)acetate 1.33 560.09 559.22 1293

N-[(1-butyl-2-phenyl-4- vinyl-1H-imidazol-5- yl)methyl]-N-(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)-N-(3- ethoxybenzyl) amine 1.2537.70 537.30 1294

methyl 4-{[[(1-butyl-2- phenyl-4-vinyl-1H- imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6- ylmethyl)amino] methyl}benzoate1.2 551.68 551.28 1295

N-[(1-butyl-4-ethyl-2- phenyl-1H-imidazol-5- yl)methyl]-N-(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)-N-(3- ethoxybenzyl) amine 1.22539.72 539.31 1296

methyl 4-{[[(1-butyl-4- ethyl-2-phenyl-1H- imidazol-5-yl)methyl](2,3-dihydro-1,4- benzodioxin-6- ylmethyl)amino] methyl}benzoate1.18 553.70 553.29 1297

(1S)-N-(1,3- benzodioxol-5- ylmethyl)-1-(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)-N-methylpentan-1- amine 1.18 509.69 509.301298

(1S)-N-(1,3- benzodioxol-5- ylmethyl)-1-(1-butyl-2,4-diphenyl-1H-imidazol-5- yl)-N-methylpentan-1- amine 1.18 509.69 509.301299

N-[(1-butyl-4-chloro-2- phenyl-1H-imidazol-5- yl)methyl]-N-(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)-N-(quinoxalin- 6-ylmethyl)amine1.29 554.09 553.22 1300

4-{[[(1-butyl-2-phenyl-4- vinyl-1H-imidazol-5- yl)methyl](2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino]methyl} benzoic acid 537.66 1301

N-{1-[1-butyl-4-chloro- 2-(2-methylphenyl)-1H- imidazol-5-yl]ethyl}-N-(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)butan-1- amine 1.16 496.09495.27 1302

N-{1-[1-butyl-4-chloro- 2-(2-methylphenyl)-1H- imidazol-5-yl]ethyl}-N-(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)-3- methylbutan-1-amine 1.18510.12 509.28 1303

N-{1-[1-butyl-4-chloro- 2-(2-methylphenyl)-1H- imidazol-5-yl]ethyl}-N-(1H-indol-5- ylmethyl)butan-1- amine 1.13 477.09 476.27 1304

N-{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}-3-methyl-N-[(2-methyl- 1H-indol-5- yl)methyl]butan-1- amine 1.15 491.12490.29 1305

1-(1-butyl-2-phenyl-1H- imidazol-5-yl)-N- (cyclohexylmethyl)-N-methylpentan-1-amine 1.11 395.63 395.33 1306

4-{[[(1-butyl-4-ethyl-2- phenyl-1H-imidazol-5- yl)methyl](2,3-dihydro-1,4-benzodioxin-6- ylmethyl)amino] methyl}benzoic acid 1.16 539.67539.28 1307

N-{[4-chloro-1- (ethoxymethyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N-(2,3- dihydro-1,4- benzodioxin-6- ylmethyl)-N-(3-ethoxybenzyl) amine 548.08 1308

N-{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl] methyl}-N-methyl-1,2,3,4- tetrahydronaphthalen-1- amine 422.01 1309

1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N- (cyclohexylmethyl)-N-(1,2,3,4- tetrahydroquinolin-6- ylmethyl) methanamine 1.2 546.80 546.371310

1-[1-butyl-2-phenyl-4- (trifluoromethyl)-1H- imidazol-5-yl]-N-(cyclohexylmethyl)-N- (1,2,3,4- tetrahydroquinolin-6-ylmethyl)methanamine 1.28 538.70 538.33 1311

N-{[4-bromo-1-butyl-2- (2,6-diethylphenyl)-1H- imidazol-5-yl]methyl}-N-methyl-1,2,3,4- tetrahydronaphthalen-1- amine 1.27 508.54 507.22 1312

methyl 4-{[{[1-butyl-4- (4-methylphenyl)-2- phenyl-1H-imidazol-5- yl]methyl}(2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino] methyl}benzoate1.22 615.77 615.31 1313

methyl 4-{[{[1-butyl-4- (3-fluorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}(2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoate 1.2 619.73 619.28 1314

4-{[{[1-butyl-4-(4- methylphenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}(2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid 1.19 601.74 601.29 1315

4-{[{[1-butyl-4-(3- fluorophenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}(2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid 1.18 605.71 605.27 1316

N-{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}-N-(3-methoxybenzyl) butan-1-amine 1.2 454.05 453.25 1317

N-{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}-N-(3-ethoxybenzyl)butan- 1-amine 1.22 468.08 467.27 1318

N-{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}-N-(1H-indol-5-ylmethyl)- 3,3-dimethylbutan-1- amine 1.14 491.12 490.291319

6-[(butyl{[1-butyl-4- chloro-2-(2- methylphenyl)-1H- imidazol-5-yl]methyl)amino)methyl]- 3,4-dihydroquinolin- 2(1H)-one 1.11 493.094492.27 1320

N-{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}-N-(1,2,3,4- tetrahydroquinolin-6- ylmethyl)butan-1- amine 1.13 479.11478.29 1321

N-{[1-butyl-4-chloro-2- (2,6-diethylphenyl)-1H- imidazol-5-yl]methyl}-N-methyl-1,2,3,4- tetrahydronaphthalen-1- amine 1.24 464.09 463.28 1322

(1S)-N-{[1-butyl-4- chloro-2-(2,6- diethylphenyl)-1H-imidazol-5-yl]methyl}-N- methyl-1,2,3,4- tetrahydronaphthalen-1- amine1.24 464.09 463.28 1323

6-{[{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}(isopentyl) amino]methyl}-3,4- dihydroquinolin-2(1H)- one 1.14507.12 506.28 1324

N-{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}-N-(2,3-dihydro-1- benzofuran-5-ylmethyl)- 3-methylbutan-1-amine 1.16480.09 479.27 1325

N-{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}-N-(4-methoxybenzyl)-3- methylbutan-1-amine 1.17 468.08 467.27 1326

N-{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}-N-(3-methoxybenzyl)-3- methylbutan-1-amine 1.21 468.08 467.27 1327

N-{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}-N-(4-ethoxybenzyl)-3- methylbutan-1-amine 1.19 482.11 481.29 1328

N-{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}-N-(3-ethoxybenzyl)-3- methylbutan-1-amine 1.23 482.11 481.29 1329

ethyl N-{[1-butyl-4- chloro-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}-N- (2,3-dihydro-1,4- benzodioxin-6-ylmethyl)-beta- alaninate 1.25 526.07 525.24 1330

4-[{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}(2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]-2-methylbutan-2-ol 1.11 512.09 511.26 1331

ethyl N-{[1-butyl-4- chloro-2-(2- methylphenyl)-1H-imidazol-5-yl]methyl}-N- (1H-indol-5-ylmethyl)- beta-alaninate 1.15507.07 506.24 1332

4-[{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}(1H-indol-5- ylmethyl)amino]-2- methylbutan-2-ol 1.1 493.09492.27 1333

N-{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}-N-[(3-chloro-1H-indol-5- yl)methyl]-3,3- dimethylbutan-1-amine 1.19 525.56524.25 1334

N-{[1-butyl-2-(2,6- diethylphenyl)-4-(4- methylphenyl)-1H-imidazol-5-yl]methyl}-N- methyl-1,2,3,4- tetrahydronaphthalene-1- amine1.26 519.77 519.36 1335

N-{[1-butyl-2-(2,6- diethylphenyl)-1H- imidazol-5-yl]methyl}-N-methyl-1,2,3,4- tetrahydronaphthalen-1- amine 1.18 429.65 429.31 1336

N-{[1-butyl-2-(2,6- diethylphenyl)-4-methyl- 1H-imidazol-5-yl]methyl}-N-methyl- 1,2,3,4- tetrahydronaphthalen-1- amine 1.2 443.68443.33 1337

methyl 4-{[{[1-butyl-4- (4-fluorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}(2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoate 1.2 619.73 619.28 1338

methyl 4-{[{[1-butyl-4- (3-methylphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}(2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoate 1.21 615.77 615.31 1339

methyl 4-{[{[1-butyl-4- (3-methoxyphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}(2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoate 1.21 631.77 631.30 1340

methyl 4-{[{[1-butyl-4- (4-methoxyphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}(2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoate 1.2 631.77 631.30 1341

methyl 4-{[{[1-butyl-4- (4-chlorophenyl)-2- phenyl-1H-imidazol-5-yl]methyl}(2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoate 1.22 636.19 635.26 1342

4-{{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}[(3-chloro-1H-indol-5- yl)methyl]amino}-2- methylbutan-2-ol 1.13 527.54526.23 1343

N-{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-4-yl]methyl}-N-(1H-indol-5-ylmethyl)- 2,2-dimethylpropan-1- amine 477.09 1344

N-{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}-N-[(3-chloro-1H-indol-5- yl)methyl]-2,2- dimethylpropan-1- amine 1.37511.54 510.23 1345

N-{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}-N-(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)-2,2- dimethylpropan-1- amine496.09 1346

N-{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}-N-(2-fluoro-4- methoxybenzyl)-3- methylbutan-1-amine 486.07 1347

N-{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}-N-(2-chloro-4- methoxybenzyl)-3- methylbutan-1-amine 502.53 1348

N-{[4-bromo-2-(2,6- diethylphenyl)-1-(1,3- dioxolan-2-ylmethyl)-1H-imidazol-5- yl]methyl}-N-methyl- 1,2,3,4- tetrahydronaphthalen-1-amine 538.53 1349

N-{[4-bromo-2-(2,6- diethylphenyl)-1- (ethoxymethyl)-1H-imidazol-5-yl]methyl}-N- methyl-1,2,3,4- tetrahydronaphthalen-1- amine510.52 1350

4-{[{[1-butyl-4-(4- fluorophenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}(2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid 605.71 1351

4-{[{[1-butyl-4-(3- methylphenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}(2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid 601.74 1352

4-{[{[1-butyl-4-(3- methoxyphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}(2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid 617.74 1353

4-{[{[1-butyl-4-(4- chlorophenyl)-2-phenyl- 1H-imidazol-5-yl]methyl}(2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid 622.16 1354

4-{[{[1-butyl-4-(4- methoxyphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}(2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid 617.74 1355

N-{[4-bromo-2-(2,6- diethylphenyl)-1-(2- morpholin-4-ylethyl)-1H-imidazol-5-yl]methyl}-N- methyl-1,2,3,4- tetrahydronaphthalen-1- amine1.16 565.60 564.25 1356

N-{[4-chloro-1-(2- morpholin-4-ylethyl)-2- phenyl-1H-imidazol-5-yl]methyl}-N-(2,3- dihydro-1,4- benzodioxin-6- ylmethyl)-N-(3-ethoxybenzyl) amine 1.2 603.16 602.27 1357

1-[4-chloro-2-phenyl-1- (2-piperidin-1-ylethyl)- 1H-imidazol-5-yl]-N-(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)-N-(3- ethoxybenzyl)methanamine 1.19 601.19 600.29 1358

methyl 4-[(butyl{[1- butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H-imidazol-5- yl]methyl}amino) methyl]benzoate 1.23 537.74 537.34 1359

methyl 4-{[{[1-butyl-2- (2-methylphenyl)-4-(4- methylphenyl)-1H-imidazol-5- yl]methyl}(isobutyl)amino] methyl}benzoate 1.24 537.74537.34 1360

methyl 4-{[{[1-butyl-2- (2-methylphenyl)-4-(4- methylphenyl)-1H-imidazol-5-yl]methyl}(2- ethylbutyl)amino]methyl} benzoate 1.27 565.80565.37 1361

methyl 4-{[{[1-butyl-2- (2-methylphenyl)-4-(4- methylphenyl)-1H-imidazol-5-yl] methyl}(isopentyl) amino]methyl} benzoate 1.25 551.77551.35 1362

methyl 4-{[{[1-butyl-2- (2-methylphenyl)-4-(4- methylphenyl)-1H-imidazol-5-yl] methyl}(cyclohexylmethyl) amino] methyl}benzoate 1.28577.81 577.37 1363

methyl 4-[(benzyl{[1- butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H-imidazol-5- yl]methyl}amino)methyl] benzoate 1.25 571.76 571.32 1364

methyl 4-{[{[1-butyl-2- (2-methylphenyl)-4-(4- methylphenyl)-1H-imidazol-5- yl]methyl}(2,3-dihydro- 1,4-benzoidoxin-6- ylmethyl)amino]methyl}benzoate 1.23 629.80 529.33 1365

methyl 4-{[{[1-butyl-2- (2-methylphenyl)-4- phenyl-1H-imidazol-5- yl]methyl}(isopentyl) amino]methyl} benzoate 1.24 537.74 537.34 1366

methyl 4-{[{[1-butyl-1- (2-methylphenyl)-4- phenyl-1H-imidazol-5- yl]methyl}(2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino] methyl}benzoate1.22 615.77 615.31 1367

methyl 4-[(benzyl{[1- butyl-2-(2- methylphenyl)-4-phenyl- 1H-imidazol-5-yl]methyl}amino) methyl]benzoate 1.22 557.73 557.30 1368

4-[(butyl{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H-imidazol-5- yl]methyl}amino) methyl]benzoic acid 1.21 523.72 523.32 1369

4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(isobutyl) amino]methyl} benzoic acid 1.21 523.72 523.32 1370

4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H-imidazol-5-yl]methyl}(2- ethylbutyl)amino] methyl}benzoic acid 1.24551.77 551.35 1371

4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(isopentyl) amino]methyl} benzoic acid 1.22 537.74 537.34 1372

4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(cyclohexylmethyl) amino] methyl}benzoic acid 1.25 563.78 563.351373

4-[(benzyl{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H-imidazol-5- yl]methyl}amino)methyl] benzoic acid 1.21 557.73 557.30 1374

N-{[4-chloro-2-(2,6- dimethylphenyl)-1- methyl-1H-imidazol-5-yl]methyl}-N-methyl- 1,2,3,4- tetrahydronaphthalene-1- amine 1.09 393.96393.20 1375

4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)amino] methyl}benzoicacid 1.2 615.77 615.31 1376

4-{[{[1-butyl-2-(2- methylphenyl)-4-phenyl- 1H-imidazol-5- yl]methyl}(isopentyl)amino]methyl} benzoic acid 523.72 1377

4-{[{[1-butyl-2-(2- methylphenyl)-4-phenyl- 1H-imidazol-5-yl]methyl}(2,3-dihydro- 1,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid 601.74 1378

4-[(benzyl{[1-butyl-2-(2- methylphenyl)-4-phenyl- 1H-imidazol-5-yl]methyl}amino) methyl]benzoic acid 543.71 1379

4-[(butyl{[1-butyl-2-(2- methylphenyl)-4-phenyl- 1H-imidazol-5-yl]methyl}amino) methyl]benzoic acid 1.19 509.69 509.30 1380

methyl 4-{[{[1-butyl-2- (2-methylphenyl)-4-(4- methylphenyl)-1H-imidazol-5- yl]methyl}(propyl) amino]methyl} benzoate 523.72 1381

methyl 4-{[{[1-butyl-2- (2-methylphenyl)-4-(4- methylphenyl)-1H-imidazol-5-yl] methyl}(neopentyl) amino]methyl} benzoate 551.77 1382

methyl 4-{[{[1-butyl-2- (2-methylphenyl)-4-(4- methylphenyl)-1H-imidazol-5- yl]methyl}(3,3- dimethylbutyl) amino]methyl} benzoate 565.801383

methyl 4-{[{[1-butyl-2- (2-methylphenyl)-4-(4- methylphenyl)-1H-imidazol-5- yl]methyl}(pentyl) amino]methyl} benzoate 551.77 1384

methyl 4-{[{[1-butyl-2- (2-methylphenyl)-4-(4- methylphenyl)-1H-imidazol-5- yl]methyl}(hexyl) amino]methyl} benzoate 565.80 1385

methyl 4-{[{[1-butyl-2- (2-methylphenyl)-4-(4- methylphenyl)-1H-imidazol-5-yl]methyl}(3- methylbut-2- enyl)amino]methyl}benzoate 549.761386

methyl 4-[((bicyclo [2.2.1]hept-5-en-2- ylmethyl){[1-butyl-2-(2-methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5- yl]methyl}amino)methyl]benzoate 587.80 1387

methyl 4-{[{[1-butyl-2- (2-methylphenyl)-4-(4- methylphenyl)-1H-imidazol-5-yl] methyl}(tetrahydrofuran- 3-ylmethyl) amino]methyl}benzoate 565.75 1388

methyl 4-{[{[1-butyl-2- (2-methylphenyl)-4-(4- methylphenyl)-1H-imidazol-5- yl]methyl}(thien-3- ylmethyl)amino] methyl}benzoate 577.791389

4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(propyl) amino]methyl} benzoic acid 1.19 509.69 509.30 1390

4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(neopentyl) amino]methyl} benzoic acid 1.23 537.74 537.34 1391

4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(3,3- dimethylbutyl) amino]methyl} benzoic acid 1.23 551.77551.35 1392

4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(pentyl)amino] methyl} benzoic acid 1.23 537.74 537.34 1393

4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(hexyl)amino] methyl}benzoic acid 1.24 551.77 551.35 1394

4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H-imidazol-5-yl]methyl}(3- methylbut-2- enyl)amino]methyl} benzoic acid1.22 535.73 535.32 1395

4-[((bicyclo[2.2.1] hept- 5-en-2-ylmethyl){[1- butyl-2-(2-methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}amino)methyl] benzoic acid 1.24 573.78 573.34 1396

4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(thien-3- ylmethyl)amino] methyl}benzoic acid 1.19 563.76563.26 1397

methyl 4-{[{[1-butyl-2- (2-methylphenyl)-4-(4- methylphenyl)-1H-imidazol-5-yl] methyl}(1H-indol-5- ylmethyl)amino] methyl}benzoate 1.27610.80 610.33 1398

4-{[{[1-butyl-2-(2- methylphenyl)-4-(4- methylphenyl)-1H- imidazol-5-yl]methyl}(1H-indol-5- ylmethyl)amino] methyl}benzoic acid 1.24 596.77596.32 1399

N-{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}-N-(1H-indazol-5-ylmethyl)- 3-methylbutan-1-amine 1.18 478.08 477.27 1400

4-{[{[1-butyl-4-(4- methoxyphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}(ethyl) amino]methyl}-2- hydroxybenzamide 1.16 512.65 512.281401

(1S)-N-{[1-butyl-4- chloro-2-(2,6- dimethylphenyl)-1H-imidazol-5-yl]methyl}-N- methyl-1,2,3,4- tetrahydronaphthalen-1- amine1.24 436.04 435.24 1402

N-{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}-N-(1H-indazol-5-ylmethyl)- 2,2-dimethylpropan-1- amine 1.31 478.08 477.271403

1-[1-butyl-4-chloro-2-(2- methylphenyl)-1H- imidazol-5-yl]-N-(1H-indazol-5-ylmethyl)-N- (3-methoxybenzyl) methanamine 1.33 528.10 527.251404

1-[1-butyl-4-chloro-2-(2- methylphenyl)-1H- imidazol-5-yl]-N-(1H-indazol-5-ylmethyl)-N- (4-methoxybenzyl) methanamine 1.29 528.10 527.251405

4-{[{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}(4-methoxybenzyl)amino] methyl}-2- hydroxybenzamide 1.28 547.10 546.24 1406

4-{[{[1-butyl-4-chloro-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}(3-methoxybenzyl)amino] methyl}-2- hydroxybenzamide 1.26 547.10 546.24 1407

4-{[{[1-butyl-4-(4- methoxyphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}(2- methoxyethyl) amino]methyl}-2- hydroxybenzamide 1.11542.68 542.29 1408

4-{[{[1-butyl-4-(4- methoxyphenyl)-2- pyridin-3-yl-1H-imidazol-5-yl]methyl} (cyclohexylmethyl)amino] methyl}-2-hydroxybenzamide 1.21 581.76 581.34 1409

7-{[{[1-butyl-4-(4- methoxyphenyl)-2- phenyl-1H-imidazol-5- yl]methyl}(neopentyl)amino] methyl}-2H-1,3- benzoxazine-2,4(3H)- dione 1.23 580.73580.30 1410

1-(1-butyl-2,4-diphenyl- 1H-imidazol-5-yl)-N- (cyclohexylmethyl}-N-(1H-indazol-5-ylmethyl) methanamine 1.26 531.74 531.34 1411

N-[(1-butyl-2,4- diphenyl-1H-imidazol-5- yl)methyl]-N-(1H-indazol-5-ylmethyl)-2,2- dimethylpropan-1- amine 1.23 505.71 505.32 1412

1-[1-butyl-4-(4- methoxyphenyl)-2- phenyl-1H-imidazol-5- yl]-N-(cyclohexylmethyl)-N- (1H-indazol-5-ylmethyl) methanamine 1.27 561.77561.35 1413

methyl 4- [((cyclohexylmethyl){[1- [2- (dimethylamino)ethyl]-4-(4-methoxyphenyl)-2- phenyl-1H-imidazol-5- yl]methyl} amino)methyl]-2-methoxybenzoate 1.19 624.82 624.37 1414

N-{[4-chloro-2-(2,6- diethylphenyl)-1-(2- methoxyethyl)-1H-imidazol-5-yl]methyl}-N- propylpropan-1-amine 1.11 406.01 405.25 1415

4- [((cyclohexylmethyl){[1- [2- (dimethylamino)ethyl]-4-(4-methoxyphenyl)-2- phenyl-1H-imidazol-5- yl]methyl}amino)methyl]-2-hydroxybenzamide 1.18 595.78 595.35 1416

1-butyl-5-{[(1H-indazol- 5- ylmethyl)(neopentyl) amino]methyl}-2-(2-methylphenyl)-1H- imidazole-4-carbonitrile 1.32 468.65 468.30 1417

1-butyl-5- {[(cyclohexylmethyl)(1H- indazol-5- ylmethyl)amino]methyl}-2-(2-methylphenyl)-1H- imidazole-4-carbonitrile 1.35 494.68 494.32 1418

N-{[4-chloro-2-(2,6- diethylphenyl)-1-(2- methoxyethyl)-1H-imidazol-5-yl]methyl}-N- (4-methoxybenzyl)-2,2- dimethylpropan-1- amine1.32 512.13 511.30 1419

4-{[{[1-butyl-4-cyano-2- (2-methylphenyl)-1H- imidazol-5-yl]methyl}(cyclohexylmethyl) amino]methyl}-2- hydroxybenzamide 1.33513.68 513.31 1420

N-{[4-chloro-2-(2,6- diethylphenyl)-1-(2- methoxyethyl)-1H-imidazol-5-yl]methyl}-N- (3-ethoxybenzyl)-2,2- dimethylpropan-1- amine1.42 526.16 525.31 1421

N-{[4-chloro-2-(2,6- diethylphenyl)-1-(2- methoxyethyl)-1H-imidazol-5-yl]methyl}-N- (cyclohexylmethyl)-2,2- dimethylpropan-1- amine1.37 488.16 487.33 1422

N-{[4-chloro-2-(2,6- diethylphenyl)-1-(2- methoxyethyl)-1H-imidazol-5-yl]methyl}-N- (cyclohexylmethyl)-2- methylpropan-2-amine 1.16474.13 473.32 1423

4-{[{[1-butyl-4-(4- methoxyphenyl)-2- pyridin-4-yl-1H- imidazol-5-yl]methyl}(cyclohexylmethyl) amino] methyl}-2- hydroxybenzamine 1.25581.76 581.34 1424

N-{[1-butyl-4-chloro-2- (2,6-dimethylphenyl)- 1H-imidazol-5-yl]methyl}-N-(4- methoxybenzyl)-2,2- dimethylpropan-1- amine 1.48 482.11481.29 1425

N-{[1-butyl-4-chloro-2- (2,6-dimethylphenyl)- 1H-imidazol-5-yl]methyl}-N-(3- ethoxybenzyl)-2,2- dimethylpropan-1- amine 1.54 496.14495.30 1426

N-{[1-butyl-4-chloro-2- (2,6-dimethylphenyl)- 1H-imidazol-5-yl]methyl}-N- (cyclohexylmethyl)-2,2- dimethylpropan-1- amine 1.57458.13 457.32 1427

N-{[1-butyl-4-chloro-2- (2,6-dimethylphenyl)- 1H-imidazol-5-yl]methyl}-N- (cyclohexylmethyl)-2- methylpropan-2-amine 1.19 444.10443.31 1428

N-(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)-N-{[1-(2-methoxyethyl)-4-(4- methoxyphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-2,2- dimethylpropan-1- amine 1.25 555.72 555.31 1429

N-(2,3-dihydro-1,4- benzodioxin-6- ylmethyl)-N-{[1-(2-methoxyethyl)-4-(4- methoxyphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}-2- methylpropan-1-amine 541.69 1430

1-cyclopropyl-N-(2,3- dihydro-1,4- benzodioxin-6- ylmethyl)-N-{[1-(2-methoxyethyl)-4-(4- methoxyphenyl)-2- phenyl-1H-imidazol-5-yl]methyl}methanamine 539.67 1431

N-benzyl-N-{[4-chloro- 2-(2,6-diethylphenyl)-1- (2-methoxyethyl)-1H-imidazol-5-yl]methyl}- 2,2-dimethylpropan-1- amine 482.11 1432

N-{[1-butyl-4-chloro-2- (2,6-dimethylphenyl)- 1H-imidazol-5-yl]methyl}-N- isopentylheptan-4- amine 460.15 1433

N-{[1-butyl-4-chloro-2- (2,6-dimethylphenyl)- 1H-imidazol-5-yl]methyl}-1-[4- (diflurormethoxy)phenyl]- N,4-dimethylpentan- 1-amine532.12 1434

ethyl (4-chloro-5-{[(4- methoxybenzyl)(neopentyl) amino]methyl}-2-phenyl-1H-imidazol-1- yl)acetate 484.04 1435

ethyl (4-chloro-5-{[(2,3- dihydro-1,4- benzodioxin-6-ylmethyl)(neopentyl) amino]methyl}-2-phenyl- 1H-imidazol-1- yl)acetate512.05 1436

N-{[4-chloro-2-(2,6- diethylphenyl)-1-(2- methoxyethyl)-1H-imidazol-5-yl] methyl}- N-(1H-indazol-5- ylmethyl)-2-methoxy- ethanamine510.078 1437

N-{[1-butyl-4-chloro-2- (2,6-dimethylphenyl)- 1H-imidazol-5-yl]methyl}-N-(1H- indazol-5-ylmethyl)-2- methoxy-ethanamine 480.053 1438

N-{[4-bromo-2-(2,6- diethylphenyl)-1-ethyl- 1H-imidazol-5-yl]methyl}-N-(4- methoxybenzyl)-2,2- dimethylpropan-1- amine 526.5591439

N-{[4-bromo-2-(2,6- diethylphenyl)-1-ethyl- 1H-imidazol-5-yl]methyl}-N-(2,3- dihydro-1,4- benzodioxin-6- ylmethyl)-2,2-dimethylpropan-1- amine 554.569 1440

2-hydroxy-4-{[{[1-(2- methoxyethyl)-4-(4- methoxyphenyl)-2-phenyl-1H-imidazol-5- yl]methyl} (neopentyl)amino] methyl}benzamide556.703

Example 44 Preparation of Radiolabeled Probe Compounds of the Invention

The compounds of the invention are prepared as radiolabeled probes bycarrying out their synthesis using precursors comprising at least oneatom that is a radioisotope. The radioisotope is preferably selectedfrom of at least one of carbon preferably ¹⁴C), hydrogen (preferably³H), sulfur (preferably ³⁵S), or iodine (preferably ¹²⁵I). Suchradiolabeled probes are conveniently synthesized by a radioisotopesupplier specializing in custom synthesis of radiolabeled probecompounds. Such suppliers include Amersham Corporation, ArlingtonHeights, Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass.; SRIInternational, Menlo Park, Calif.; Wizard Laboratories, West Sacramento,Calif.; ChemSyn Laboratories, Lexena, Kans.; American RadiolabeledChemicals, Inc., St. Louis, Mo.; and Moravek Biochemicals Inc., Brea,Calif.

Tritium labeled probe compounds are also conveniently preparedcatalytically via platinum-catalyzed exchange in tritiated acetic acid,acid-catalyzed exchange in tritiated trifluoroacetic acid, orheterogeneous-catalyzed exchange with tritium gas. Such preparations arealso conveniently carried out as a custom radiolabeling by any of thesuppliers listed in the preceding paragraph using the compound of theinvention as substrate. In addition, certain precursors may be subjectedto tritium-halogen exchange with tritium gas, tritium gas reduction ofunsaturated bonds, or reduction using sodium borotritide, asappropriate.

Example 45 Receptor autoradiography

Receptor autoradiography (receptor mapping) is carried out in vitro asdescribed by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols inPharmacology (1998) John Wiley & Sons, New York, using radiolabeledcompounds of the invention prepared as described in the precedingExamples.

Example 46 Assay for C5a Receptor Mediated Chemotaxis

This assay is a standard assay of C5a receptor mediated chemotaxis.

Human promonocytic U937 cells or purified human or non-human neutrophilsare treated with dibutyryl cAMP for 48 hours prior to performing theassay. Human neutrophils or those from another mammalian species areused directly after isolation. The cells are pelleted and resuspended inculture media containing 0.1% fetal bovine serum (FBS) and 10 ug/mlcalcein AM (a fluorescent dye). This suspension is then incubated at 37°C. for 30 minutes such that the cells take up the fluorescent dye. Thesuspension is then centrifuged briefly to pellet the cells, which arethen resuspended in culture media containing 0.1% FBS at a concentrationof approximately 3×10⁶ cells/mL. Aliquots of this cell suspension aretransferred to clean test tubes, which contain vehicle (1% DMSO) orvarying concentrations of a compound of interest, and incubated at roomtemperature for at least 30 minutes. The chemotaxis assay is performedin CHEMO TX 101-8, 96 well plates (Neuro Probe, Inc. Gaithersburg, Md.).The bottom wells of the plate are filled with medium containing 0-10 nMof C5a, preferably derived from the same species of mammal as are theneutrophils or other cells (e.g., human C5a for the human U937 cells).The top wells of the plate are filled with cell suspensions (compound orvehicle-treated). The plate is then placed in a tissue culture incubatorfor 60 minutes. The top surface of the plate is washed with PBS toremove excess cell suspension. The number of cells that have migratedinto the bottom well is then determined using a fluorescence reader.Chemotaxis index (the ratio of migrated cells to total number of cellsloaded) is then calculated for each compound concentration to determinean IC₅₀ value.

As a control to ensure that cells retain chemotactic ability in thepresence of the compound of interest, the bottom wells of the plate maybe filled with varying concentrations chemo-attractants that do notmediate chemotaxis via the C5a receptor (e.g. zymosan-activated serum(ZAS), N-formylmethionyl-leucyl-phenylalanine (FMLP) or leukotriene B4(LTB4)), rather than C5a, under which conditions the compounds providedherein preferably do not inhibit chemotaxis.

Preferred compounds exhibit IC₅₀ values of less than 1 μM in the aboveassay for C5a receptor mediated chemotaxis.

Example 47 Expression of a C5a Receptor

A human C5a receptor cDNA is obtained by PCR using 1) a forward primeradding a Kozak ribosome binding site and 2) a reverse primer that addedno additional sequence, and 3) an aliquot of a Stratagene Human FetalBrain cDNA library as template. The sequence of the resulting PCRproduct is as described by Gerard and Gerard, (1991) Mature 349:614-17.The PCR product is subcloned into the cloning vector pCR-Script(STRATAGENE, La Jolla, Calif.) at the Srf I site. It is then excisedusing the restriction enzymes EcoRI and NotI and subcloned in theappropriate orientation for expression into the baculoviral expressionvector pBacPAK 9 (CLONTECH, Palo Alto, Calif.) that has been digestedwith EcoRI and NotI.

Example 48 Baculoviral Preparations for C5a Expression

The human C5a (hC5a) receptor baculoviral expression vector isco-transfected along with BACULOGOLD DNA (BD PharMingen, San Diego,Calif.) into Sf9 cells. The Sf9 cell culture supernatant is harvestedthree days post-transfection. The recombinant virus-containingsupernatant is serially diluted in Hink's TNM-FH insect medium (JRHBiosciences, Lenexa, Kans.) supplemented Grace's salts and with 4.1 mML-Gln, 3.3 g/L LAH, 3.3 g/L ultrafiltered yeastolate and 10%heat-inactivated fetal bovine serum (hereinafter “insect medium”) andplaque assayed for recombinant plaques. After four days, recombinantplaques are selected and harvested into 1 ml of insect medium foramplification. Each 1 ml volume of recombinant baculovirus (at passage0) is used to infect a separate T25 flask containing 2×10⁶ Sf9 cells in5 mls of insect medium. After five days of incubation at 27° C.,supernatant medium is harvested from each of the T25 infections for useas passage 1 inoculum.

Two of seven recombinant baculoviral clones are then chosen for a secondround of amplification, using 1 ml of passage 1 stock to infect 1×10⁸cells in 100 ml of insect medium divided into 2 T175 flasks. Forty-eighthours post infection, passage 2 medium from each 100 ml prep isharvested and plaque assayed for titer. The cell pellets from is thesecond round of amplification are assayed by affinity binding asdescribed below to verify recombinant receptor expression. A third roundof amplification is then initiated using a multiplicity of infection of0.1 to infect a liter of Sf9 cells. Forty hours post-infection thesupernatant medium is harvested to yield passage 3 baculoviral stock.

The remaining cell pellet is assayed for affinity binding using the“Binding Assays” essentially as described by DeMartino et al., (1994) J.Biol. Chem. 269:1446-50 at page 14447, adapted as follows. Radioligandis 0.005-0.500nM [¹²⁵I]C5a (human recombinant; New England NuclearCorp., Boston, Mass.); the hC5a receptor-expressing baculoviral cellsare used instead of 293 cells; the assay buffer contains 50 mM Hepes pH.7.6, 1 mM CaCl₂, 5 mM MgCl₂, 0.1% BSA, pH 7.4, 0.1 mM bacitracin, and100 KIU/ml aprotinin; filtration is carried out using GF/C WHATMANfilters (presoaked in 1.0% polyethyleneimine for 2 hours prior to use);and the filters are washed twice with 5 mLs cold binding buffer withoutBSA, bacitracin, or aprotinin.

Titer of the passage 3 baculoviral stock is determined by plaque assayand a multiplicity of infection, incubation time course, binding assayexperiment is carried out to determine conditions for optimal receptorexpression. A multiplicity of infection of 0.1 and a 72-hour incubationwere the best infection parameters found for hC5a receptor expression inup to 1-liter Sf9 cell infection cultures.

Example 49 Baculoviral Infections

Log-phase Sf9 cells (INVITROGEN Corp., Carlsbad Calif.) are infectedwith one or more stocks of recombinant baculovirus followed by culturingin insect medium at 27° C. Infections are carried out either only withvirus directing the expression of the hC5a receptor or with this virusin combination with three G-protein subunit-expression virus stocks: 1)rat Gα_(i2) G-protein-encoding virus stock (BIOSIGNAL #V5J008), 2)bovine b1 G-protein-encoding virus stock (BIOSIGNAL #V5H012), and 3)human g2 G-protein-encoding virus stock (BIOSIGNAL #V6B003), all ofwhich may be obtained from BIOSIGNAL Inc. (Montreal, Canada).

The infections are conveniently carried out at a multiplicity ofinfection of 0.1:1.0:0.5:0.5. At 72 hours post-infection a sample ofcell suspension is analyzed for viability by trypan blue dye exclusion,and the remaining Sf9 cells are harvested via centrifugation (3000rpm/10 minutes/4° C.).

Example 50 Purified Recombinant Insect Cell Membranes

Sf9 cell pellets are resuspended in homogenization buffer (10 mM HEPES,250 mM sucrose, 0.5 ug/ml leupeptin, 2 ug/ml Aprotinin, 200 uM PMSF, and2.5 mM EDTA, pH 7.4) and homogenized using a POLYTRON homogenizer(setting 5 for 30 seconds). The homogenate is centrifuged (536× g/10minutes/4° C.) to pellet the nuclei. The supernatant containing isolatedmembranes is decanted to a clean centrifuge tube, centrifuged (48,000×g/30 minutes, 4° C.) and the resulting pellet resuspended in 30 mlhomogenization buffer. This centrifugation and resuspension step isrepeated twice. The final pellet is resuspended in ice cold Dulbecco'sPBS containing 5 mM EDTA and stored in frozen aliquots at −80° C. untilneeded. The protein concentration of the resulting membrane preparation(hereinafter “P2 membranes”) is conveniently measured using a Bradfordprotein assay (Bio-Rad Laboratories, Hercules, Calif.). By this measure,a 1-liter culture of cells typically yields 100-150 mg of total membraneprotein.

Example 51 Radioligand Biding Assays

Purified P2 membranes, prepared by the method given above, areresuspended by Dounce homogenization (tight pestle) in binding buffer(50 mM Hepes pH. 7.6, 120 mM NaCl, 1 mM CaCl₂, 5 mM MgCl₂, 0.1% BSA, pH7.4, 0.1 mM bacitracin, 100 KIU/ml aprotinin).

For saturation binding analysis, membranes (5-50 μg) are added topolypropylene tubes containing 0.005-0.500 nM [¹²⁵I]C5a (human(recombinant), New England Nuclear Corp., Boston, Mass.). Nonspecificbinding is determined in the presence of 300 nM hC5a (Sigma ChemicalCo., St. Louis, Mo.) and accounts for less than 10% of total binding.For evaluation of guanine nucleotide effects on receptor affinity, GTPγSis added to duplicate tubes at the final concentration of 50 μM.

For competition analysis, membranes (5-50 μg) are added to polypropylenetubes containing 0.030 nM [¹²⁵I]C5a (human). Non-radiolabeled displacersare added to separate assays at concentrations ranging from 10⁻¹⁰ M to10⁻⁵ M to yield a final volume of 0.250 mL. Nonspecific binding isdetermined in the presence of 300 nM hC5a (Sigma Chemical Co., St.Louis, Mo.) and accounts for less than 10% of total binding. Following a2-hour incubation at room temperature, the reaction is terminated byrapid vacuum filtration. Samples are filtered over presoaked (in 1.0%polyethyleneimine for 2 hours prior to use) GF/C WHATMAN filters andrinsed 2 times with 5 mLs cold binding buffer without BSA, bacitracin,or aprotinin. Reining bound radioactivity is quantified by gammacounting. K₁ and Hill coefficient (“nH”) are determined by fitting theHill equation to the measured values with the aid of SIGMAPLOT software(SPSS Inc., Chicago, Ill.).

Example 52 Agonist-Induced GTP Binding

Agonist-stimulated GTP-gamma³⁵S binding (“GTP binding”) activity can beused to identify agonist and antagonist compounds and to differentiateneutral antagonist compounds from those that possess inverse agonistactivity. This activity can also be used to detect partial agonismmediated by antagonist compounds. A compound being analyzed in thisassay is referred to herein as a “test compound.” Agonist-stimulated GTPbinding activity is measured as follows: Four independent baculoviralstocks (One directing the expression of the hC5a receptor and threedirecting the expression of each of the three subunits of aheterotrimeric G-protein) are used to infect a culture of Sf9 cells asdescribed in Example 49.

Agonist-stimulated GTP binding on purified membranes (prepared asdescribed in Example 50) is assessed using hC5a (Sigma Chemical Co., St.Louis, Mo.) as agonist in order to ascertain that thereceptor/G-protein-alpha-beta-gamma combination(s) yield a functionalresponse as measured by GTP binding.

P2 membranes are resuspended by Dounce homogenization (tight pestle) inGTP binding assay buffer (50 mM Tris pH 7.0, 120 mM NaCl, 2 mM MgCl2, 2mM EGTA, 0.1% BSA, 0.1 mM bacitracin, 100 KIU/mL aprotinin, 5 μM GDP)and added to reaction tubes at a concentration of 30 μg protein/reactiontube. After adding increasing doses of the agonist hC5a atconcentrations ranging from 10⁻¹² M to 10⁻⁶ M, reactions are initiatedby the addition of 100 pM GTP-gamma ³⁵S. In competition experiments,non-radiolabeled test compounds are added to separate assays atconcentrations ranging from 10⁻¹⁰ M to 10⁻⁵ M along with 10 nM hC5a toyield a final volume of 0.25 mL.

Neutral antagonists are those test compounds that reduce theC5a-stimulated GTP binding activity towards, but not below, baseline(the level of GTP bound by membranes in this assay in the absence ofadded C5a or other agonist and in the further absence of any testcompound).

In contrast, in the absence of added C5a certain preferred compoundswill reduce the GTP binding activity of the receptor-containingmembranes below baseline, and are thus characterized as inverseagonists. If a test compound that displays antagonist activity does notreduce the GAP binding activity below baseline in the absence of the C5aagonist, it is characterized as a neutral antagonist.

An antagonist test compound that elevates GTP binding activity abovebaseline in the absence of added hC5a in this GYP binding assay ischaracterized as having partial agonist activity. Preferred antagonistcompounds do not elevate GTP binding activity under such conditions morethan 10%, 5% or 2% above baseline.

Following a 60-minute incubation at room temperature, the reactions areterminated by vacuum filtration over GF/C filters (pre-soaked in washbuffer, 0.1% B3SA) followed by washing with ice-cold wash buffer (50 mMTris pH 7.0, 120 mM NaCl). The amount of receptor-bound (and therebymembrane-bound) GTP-gamma ³⁵S is determined by measuring the boundradioactivity, preferably by liquid scintillation spectrometry of thewashed filters. Non-specific binding is determined using 10 mM GTP-gamma³⁵S and typically represents less than 5 percent of total binding. Datais expressed as percent above basal (baseline). The results of these GTPbinding experiments may be conveniently analyzed using SIGMAPLOTsoftware.

Example 53 Calcium Mobilization Assays

A. Response to C5a

U937 cells are grown in differentiation media (1 mM dibutyrl cAMP inRPMI 1640 medium containing 10% fetal bovine serum) for 48 hrs at 37° C.then reseeded onto 96-well plates suitable for use in a FLAPR™ PlateReader (Molecular Devices Corp., Sunnyvale Calif.). Cells are grown anadditional 24 hours (to 70-90% confluence) before the assay. The cellsare then washed once with Krebs Ringer solution. FLUO-3 calciumsensitive dye (Molecular Probes, A&. Eugene, Oreg.) is added to 10 μg/mLand incubated with the cells at room temperature for 1 to 2 hours. The96 well plates are then washed to remove excess dye. Fluorescenceresponses, measured by excitation at 480 nM and emission at 530 nM, aremonitored upon the addition of human C5a to the cells to a finalconcentration of 0.01-30.0 nM, using the FLIPR™ device (MolecularDevices). Differentiated U937 cells typically exhibit signals of5,000-50,000 Arbitrary Fluorescent Light Units in response to agoniststimulation.

B. Assays for Determination of ATP Responses

Differentiated U937 cells (prepared and tested as described above under“A. Response to C5a”) are stimulated by the addition of ATP (rather thanC5a) to a final concentration of 0.01 to 30 μM. This stimulationtypically triggers a signal of 1,000 to 12,000 arbitrary fluorescencelight units. Certain preferred compounds produce less than a 10%, lessthan a 5%, or less than a 2% alteration of this calcium mobilizationsignal when this control assay is carried out in the presence of thecompound, as compared to the signal when the assay is performed in theabsence of the compound.

C. Assays for the Identification of Receptor Modulatory Agents:Antagonists mid Agonists

The calcium mobilization assay described above may be readily adaptedfor identifying test compounds that have agonist or antagonist activityat the human C5a receptor.

For example, in order to identify antagonist compounds, differentiatedU937 cells are washed and incubated with Fluo-3 dye as described above.One hour prior to measuring the fluorescence signal, a subset of thecells is incubated with 1 μM of at least one compound to be tested. Thefluorescence response upon the subsequent addition of 0.3 nM (finalconcentration) human recombinant C5a is monitored using the FLIPR™ platereader. Antagonist compounds elicit at least a 2-fold decrease in thefluorescence response relative to that measured in the presence of humanC5a alone. Preferred antagonist compounds elicit at least a 5-fold,preferably at least a 10-fold, and more preferably at least a 20-folddecrease in the fluorescence response relative to that measured in thepresence of human C5a alone. Agonist compounds elicit an increase influorescence without the addition of C5a, which increase will be atleast partially blocked by a known C5a receptor antagonist.

Example 53 Assays to Evaluate Agonist Activity of Small Molecule C5aReceptor Antagonists

Preferred compounds provided herein are C5a receptor antagonists that donot possess significant (e.g., greater than 5%) agonist activity in anyof the C5a mediated functional assays discussed herein. Specifically,this undesired agonist activity can be evaluated, for example, in theGTP binding assay of Example 52, by measuring small molecule mediatedGTP binding in the absence of the natural agonist, C5a. Similarly, in acalcium mobilization assay (e.g., that of Example 53), a small moleculecompound can be directly assayed for the ability of the compound tostimulate calcium levels in the absence of the natural agonist, C5a. Thepreferred extent of C5a agonist activity exhibited by compounds providedherein is less than 10%, more preferably less than 5% and mostpreferably less than 2% of the response elicited by the natural agonist,C5a.

The foregoing description is illustrative thereof and it will beunderstood that variations and modifications can be effected withoutdeparting from the scope or spirit of the invention as set forth in thefollowing Claims.

What is claimed is:
 1. A packaged pharmaceutical preparation,comprising: (a) a pharmaceutical composition comprising at least onecompound of the formula:

or a pharmaceutically acceptable salt thereof, in combination with aphysiologically acceptable carrier or excipient, in a container; and (b)instructions for using the composition to treat a patient suffering fromstroke, myocardial infarction, atherosclerosis, ischemic heart disease,rheumatoid arthritis, psoriasis, cardiovascular disease, reperfusioninjury, or bronchial asthma, wherein the ring system represented by

is a 5 membered heteroaryl ring system, in which x is 0, A and E areindependently carbon or nitrogen, and G is carbon, R₁ is i) hydrogen,hydroxy, halogen, amino, cyano, nitro, —CHO, —CONH₂, C₁-C₆haloalkyl,C₁-C₆ haloalkoxy, ii) C₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆alkynyl,C₁-C₆alkanoyl, C₁-C₆alkoxy, C₁-C₇cycloalkyl,(C₃-C₇cycloalkyl)C₁-C₄alkyl, mono- or di-C₁-C₆alkylamino, mono- ordi-C₁-C₆alkylaminoC₁-C₆alkyl, mono- or di-C₁-C₆alkylcarboxamide,C₁-C₆alkoxycarbonyl, SO_(n)(C₁-C₆alkyl), —NHSO_(n) C₁-C₆alkyl,—SO_(n)N(C₁-C₆alkyl) (C₁-C₆alkyl), phenyl-SO_(n), each of which isoptionally substituted, or iii) naphthyl, phenyl, phenylC₁-C₄carbhydryl,a 5 or 6 membered heteroaryl group, or a 5 or 6 memberedheteroarylC₁-C₄carbhydryl group, each of which is optionallysubstituted; R₂, when E is Nitrogen, is chosen from optionallysubstituted C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl,C₃-C₇cycloalkyl(C₁-C₄alkyl), benzyl and C₁-C₆haloalkyl; R₂ when E isCarbon, is chosen from hydrogen, halogen, hydroxy, optionallysubstituted C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₁-C₇ alkoxy,C₁-C₇alkylamino, C₃-C₇cycloalkyl(C₁-C₄alkyl), benzyl, C₁-C₆haloalkyl,and C₁-C₆haloalkoxy; R₃ is hydrogen, C₁-C₆alkyl, C₂-C₆ alkenyl,hydroxyC₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl,(C₃-C₇cycloalkyl)C₁-C₄alkyl, or phenyl(C₁-C₄alkyl); R₄ representsC₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, C₃-C₇cycloalkenyl, (C₃-C₇cycloalkyl)C₁-C₄alkyl,(C₃-C₇cycloalkenyl)C₁-C₄alkyl, or hexahydro-1,3-benzodioxolylmethyl,each of which is optionally substituted; or R₄ represents an optionallysubstituted arylC₀-C₄alkyl group having from 1 to 2 fused or pendantrings, an optionally substituted arylC₁-C₄alkyl group, wherein the arylportion is fused to a 5 to 7 membered saturated or partially unsaturatedring, said saturated or partially unsaturated ring having 0, 1, or 2ring atoms chosen from N, O, and S with remaining ring atoms beingcarbon, an optionally substituted heterocycloalkyl(C₀-C₄alkyl) group, anoptionally substituted heteroarylC₀-C₂alkyl group, having from 1 to 2fused or pendant rings, from 5 to 7 members in each ring, and in atleast one ring 1 to 3 heteroatoms selected from the group consisting ofN, O, and S, or an optionally substituted saturated or partiallyunsaturated heterocyclic(C₀-C₄alkyl) group having from 4 to 7 ringmembers, 1 or 2 of which ring members are N, S or O, with remaining ringmembers being carbon; R₅ and R₆ are independently chosen from hydrogenand C₁-C₆alkyl, and z is 1, 2, or 3; Ar₁ represents (i) optionallysubstituted aryl, (ii) optionally substituted phenyl group fused to a 5to 7 membered saturated or partially unsaturated ring that (a) has 0, 1,or 2 ring atoms independently chosen from N, O and S, with the remainingring atoms being carbon, and (b) is substituted with from 0 to 3substituents independently chosen from halogen, alkyl, alkoxy,haloalkyl, and haloalkoxy, or (iii) optionally substituted heteroaryl,having 1 ring or 2 fused or pendant rings, from 5 to 7 members in eachring, and in at least one ring 1 to 3 heteroatoms selected from N, O,and S; Ar₂ is a salicylamide group of the formula:

each n is independently chosen from 0, 1; or 2; and y is
 1. 2. Apackaged pharmaceutical preparation, comprising: (a) a pharmaceuticalcomposition comprising a compound of the formula:

or a pharmaceutically acceptable salt thereof, in combination with aphysiologically acceptable carrier or excipient, in a container; and (b)instructions for using the composition to treat rheumatoid arthritis,psoriasis, stroke, cardiovascular disease, bronchial asthma, myocardialinfarction, atherosclerosis, ischemic heart disease, orischemia-reperfusion injury.
 3. A packaged pharmaceutical preparationaccording to claim 1 wherein: R₁ is i) hydrogen, hydroxy, halogen,amino, cyano, nitro, —CHO, —CONH₂, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, ii)C₁-C₆ alkyl, C₁-C₆alkenyl, C₁-C₆alkynyl, C₁-C₆alkanoyl, C₁-C₆ alkoxy,C₃-C₇cycloalkyl, (C₃-C₇cycloalkyl)C₁-C₄alkyl, mono- ordi-C₁-C₆alkylamino, mono- or di-C₁-C₆alkylamino C₁-C₆alkyl, mono- ordi-C₁-C₆alkylcarboxamide, C₁-₆alkoxycarbonyl, —NHSO_(n)C₁-C₆alkyl,—SO_(n)(C₁-C₆alkyl), —(C₁-₆alkyl)SO_(n)(C₁-C₆alkyl),—SO_(n)N(C₁-C₆alkyl) (C₁-C₆alkyl), phenyl-SO_(n)—, each of which isoptionally substituted with from 1 to 3 groups independently chosen fromhydrogen, hydroxy, halogen, amino, cyano, oxo, C₁-C₄alkyl, C₁-C₄alkoxy,and C₁-C₂alkoxycarbonyl, or iii) naphthyl, phenyl, phenylC₁-C₄carbhydryl, a 5 or 6 membered heteroaryl group, or a 5 or 6 memberedheteroarylC₁-C₄carbhydryl group, wherein the heteroaryl group is chosenfrom imidazolyl, pyridyl, thiazolyl, pyrimidinyl, or thienyl, each ofwhich naphthyl, phenyl, phenylC₁-C₄ carbhydryl, 5 or 6 memberedheteroaryl group, or 5 or 6 membered heteroarylC₁-C₄carbhydryl group isoptionally substituted with from 1 to 3 groups independently chosen fromhydroxy, halogen, amino, cyano, nitro, —COON, —CONH₂, —SO₂NH₂, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C₁-₆ alkyl, C₁-C₆alkoxy, 1,3-dioxol-5-yl,C₁-C₆alkanoyl, C₁-C₆alkylsulfonyl, C₁-C₆alkylsulfinyl, C₁-C₆alkylthio,C₂-C₆alkanone; C₁-C₆alkanoyl; C₂-C₆alkyl ether; C₁-C₆ alkanoyloxy;C₁-C₆alkoxycarbonyl, and C₁-C₆alkylcarboxamide; R₂, when E is Nitrogen,is chosen from C₁-C₇ alkyl, optionally substituted with from 1 to 3groups independently chosen from hydrogen, hydroxy, halogen, amino,cyano, oxo, C₁-C₄alkyl, and C₁-C₄alkoxy; C₂-C₇ alkenyl; C₂-C₇ alkynyl;C₃-C₇cycloalkyl(C₁-C₄alkyl); benzyl; and C₁-C₆haloalkyl; R₂, when E isCarbon, is chosen from hydrogen; halogen; hydroxy; C₁-C₇ alkyloptionally substituted with from 1 to 3 groups independently chosen fromhydrogen, hydroxy, halogen, amino, cyano, oxo, C₁-C₄alkyl, andC₁-C₄alkoxy; C₂-₇ alkenyl; C₂-C₇ alkynyl; C₁-C₇ alkoxy; C₁-C₇alkylamino;C₃-C₇cycloalkyl(C₁-C₄alkyl); benzyl; C₁-C₆haloalkyl; andC₁-C₆haloalkoxy; R₄ represents C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₇ cycloalkyl, C₃-C₇ cycloalkenyl, (C₃-C₇cycloalkyl)C₁-C₄alkyl,(C₃-C₇cycloalkenyl)C₁-C₄alkyl, or hexahydro-1,3-benzodioxolylmethyl,each of which is optionally substituted with from 1 to 3 groupsindependently chosen from hydrogen, hydroxy, halogen, amino, cyano,C₁-C₂alkyl, C₁-C₂alkoxy, or C₁-C₂alkoxycarbonyl; or R₄ represents a) anarylC₀-C₄alkyl group having from 1 to 2 fused or pendant rings, b) abenzyl group fused to a 5 to 7 membered saturated or partiallyunsaturated ring, said saturated or partially unsaturated ring having 0,1, or 2 ring atoms chosen from N, O, and S with remaining ring atomsbeing carbon, c) a heterocycloalkyl(C₀-C₄alkyl) group, or d) aheteroarylC₀-C₄alkyl group, having from 1 to 2 fused or pendant rings,from 5 to 7 members in each ring, and in at least one ring 1 to 3heteroatoms selected from the group consisting of N, O, and S, whereineach of a), b) c) and d) are optionally substituted with from 1 to 4groups independently chosen from hydroxy, halogen, amino, cyano, nitro,—COOH, —CONH₂, —SO₂NH₂, oxo, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy,C₁-C₆alkyl, C₁-C₆alkoxy, mono- or di-(C₁-C₆)alkylamino, C₁-C₆alkanoyl,C₁-C₆sulfonate, C₁-C₆alkylsulfonyl, C₁-C₆alkylsulfinyl, C₁-C₆alkylthio,C₂-C₆alkanone, C₂-C₆alkyl ether; C₁-C₆ alkanoyloxy; C₁-C₆alkoxycarbonyl,and C₁-C₆alkylcarboxamide; Ar, represents (i) optionally substitutedaryl, (ii) optionally substituted phenyl group fused to a 5 to 7membered saturated or partially unsaturated ring that (a) has 0, 1, or 2ring atoms independently chosen from N, O and S, with the remaining ringatoms being carbon, and (b) is substituted with from 0 to 3 substituentsindependently chosen from halogen, alkyl, alkoxy, haloalkyl, andhaloalkoxy, or (iii) optionally substituted heteroaryl, having 1 ring or2 fused or pendant rings, from 5 to 7 members in each ring, and in atleast one ring 1 to 3 heteroatoms selected from N, O, and S; Ar₂ is asalicylamide group of the formula:


4. A packaged pharmaceutical preparation according to claim 3 wherein: xis 0; A and G are carbon; E is nitrogen; and R₁ and R₃ are not joined toform a cycloalkyl ring.
 5. A packaged pharmaceutical preparationaccording to claim 3 wherein: z is 1 and R₅ is hydrogen, R₆ is hydrogen,methyl, or ethyl.
 6. A packaged pharmaceutical preparation according toclaim 3 wherein: z is 1 and R₅ is hydrogen, R₆ is hydrogen, methyl, orethyl; and Ar₁ is phenyl, pyrazolyl, or thienyl, each of which isoptionally substituted with from 1 to 2 groups independently chosen fromhalogen, hydroxy, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂haloalkyl, andC₁-C₂haloalkoxy.
 7. A packaged pharmaceutical preparation according toclaim 3 wherein: z is 1, R₅ and R₆ are hydrogen, and Ar₁ isunsubstituted phenyl or unsubstituted thienyl.
 8. A packagedpharmaceutical preparation according to claim 3 wherein: R₁ is phenyloptionally substituted with from 1 to 4 groups independently chosen fromhydroxy, halogen, amino, cyano, nitro, —COOH, —CONH₂, —SO₂NH₂, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ alkyl, C₁-C₆alkoxy, 1,3-dioxo-5-yl,C₁-C₆alkanoyl, C₁-C₆alkylsulfonyl, C₁-C₆alkylsulfinyl, C₁-C₆alkylthio,C₂-C₆alkanone; C₁-C₆alkanoyl; C₂-C₆alkyl ether; C₁-C₆ alkanoyloxy;C₁-C₆alkoxycarbonyl, and C₁-C₆alkylcarboxamide.
 9. A packagedpharmaceutical preparation according to claim 3 wherein: R₁ is phenyloptionally substituted with from 1 to 2 groups independently chosen fromhydroxy, halogen, amino, cyano, nitro, —COOH, —CONH₂, —SO₂NH₂, C₁-C₂haloalkyl, C₁-C₂ haloalkoxy, C₁-C₂alkyl, and C₁-C₂alkoxy.
 10. A packagedpharmaceutical preparation according to claim 3 wherein: R₁ isunsubstituted phenyl.
 11. A packaged pharmaceutical preparationaccording to claim 3 wherein: R₁, is thienyl or pyridyl, each of whichis optionally substituted with from 1 to 2 groups independently chosenfrom hydroxy, halogen, amino, cyano, nitro, —COOH, —CONH₂, —SO₂NH₂,C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, C₁-C₂alkyl, and C₁-C₂alkoxy.
 12. Apackaged pharmaceutical preparation according to claim 3 wherein: R, ishydrogen or halogen.
 13. A packaged pharmaceutical preparation accordingto claim 3 wherein: R₁ is halogen, C₁-C₄alkyl, C₁-C₄alkoxy, cyano,trifluoromethyl, pentafluoroethyl, difluoromethyl, trifluoromethoxy,difluoromethoxy, C₁-C₂alkylaminoC₁-C₂alkyl, hydroxymethyl, orhydroxyethyl.